Trial of Pimasertib in Hematological Malignancies
Sponsor
EMD Serono (Industry)
Overall Status
Terminated
CT.gov ID
NCT00957580
Collaborator
(none)
81
9
5
39
9
0.2
Study Details
Study Description
Brief Summary
This is an open-label, multi-center, dose-escalation trial of pimasertib (MSC1936369B) in blood and bone marrow cancers. The trial will be conducted in two parts:
Part 1 (safety run-in period): Will determine the maximum tolerated dose (MTD) of the study drug in subjects with advanced hematological malignancies.
Part 2: Will assess the anti-leukemic activity of the study drug in older subjects with newly diagnosed poor prognosis acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
81 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase II Trial With Safety-Run-In of MEK Inhibitor MSC1936369B in Subjects With Poor Prognosis Acute Myeloid Leukemia and Other Hematological Malignancies
Actual Study Start Date
:
Sep 30, 2009
Actual Primary Completion Date
:
Dec 31, 2012
Actual Study Completion Date
:
Dec 31, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Regimen 1 (Part 1)
|
Drug: Pimasertib
Pimasertib will be administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose will be escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Names:
|
| Experimental: Regimen 2 (Part 1)
|
Drug: Pimasertib
Pimasertib will be administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose will be escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Names:
|
| Experimental: Regimen 3 (Part 1)
|
Drug: Pimasertib
Pimasertib will be administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose escalation will proceed to 75 mg BID until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Names:
|
| Experimental: Regimen 1 (Part 2)
|
Drug: Pimasertib
Pimasertib will be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Names:
|
| Experimental: Regimen 2 (Part 2)
|
Drug: Pimasertib
Pimasertib will be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs) [Baseline Up to Day 29 of Cycle 1]
The DLT was any toxicity that resulted in treatment delay for more than (>) 2 weeks due to treatment-related adverse effects, or any Grade greater than or equal to (>=) 3 non-hematological toxicity excluding Grade 4 asymptomatic increases in liver function tests reversible within 7 days in subjects with liver involvement, and Grade 3 asymptomatic increases in liver function tests reversible within 7 days for subjects without liver involvement, Grade 3 vomiting unless encountered and persistent for more than 3 days despite adequate and optimal therapy, and Grade 3 diarrhea unless encountered and persistent for more than 3 days despite adequate and optimal anti-diarrhea therapy at any DL and judged to be possibly or probably related to the trial treatment by the Investigator and/or the Sponsor.
- Part 2: Percentage of Subjects With Best Overall Response [Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012]
The best overall response was to be reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) >1.0x10^9 per liter (/L), platelets >100x10^9 /L, bone marrow aspirate with less than or equal to (<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC >1.0x10^9/L, platelets >100x10^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (<) 5%. (4) Progressive disease (PD) = >50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = subjects who failed to achieve CR, CRi or PR and without criteria for PD.
Secondary Outcome Measures
- Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation [Baseline up to 3 years]
An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs include both SAEs and non-SAEs.
- Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
- Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).]
- Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
- Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)]
- Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination.
- Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).]
The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination.
- Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
- Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).]
- Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity.
- Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)]
The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity.
- Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome.
- Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
- Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)]
Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed.
- Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome.
- Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose [Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3]
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.
- Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose [Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)]
Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed.
- Part 1: Percentage of Subjects With Best Overall Response [Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012]
The best overall response was reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) >1.0x10^9 per liter (/L), platelets >100x10^9 /L, bone marrow aspirate with less than or equal to (<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC >1.0x10^9/L, platelets >100x10^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (<) 5%. (4) Progressive disease (PD) = >50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = Subjects who failed to achieve CR, CRi or PR and without criteria for PD.
- Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation [Up to 3 years]
An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
Part 1:
- Subjects with one of the following conditions:
- Primary or secondary AML, pathologically confirmed according to World Health Organization (WHO) classification who meet at least one of the following conditions:
-
Subjects with second or subsequent relapse after standard therapy, for whom no established treatment options are available
-
Subjects refractory to available therapies, for example, who failed to achieve complete response (CR) after 2 induction chemotherapy treatments
-
Newly-diagnosed older subjects (greater than or equal to 75 years of age), not candidates for intensive chemotherapy
-
Subjects with myelodysplastic syndrome (MDS), International Prognostic Scoring System (IPSS) Int-2 or high risk who are resistant or intolerant to standard treatment and not candidates for transplantation
-
Subjects with relapsed or refractory multiple myeloma (MM), who have failed or are intolerant to at least two prior therapies including thalidomide, lenalidomide and bortezomib
-
Subjects with advanced myeloproliferative disorders (MPD) for whom no established treatment options are available
-
Subjects with acute lymphocytic leukemia (ALL), relapsed, refractory or intolerant to standard treatment and for whom no effective treatment options are available
-
Age greater than or equal to 18 years
-
Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments
-
Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator, two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age
Part 2:
- Subjects (male and female) with newly diagnosed primary or secondary AML pathologically confirmed according to WHO classification who have not been exposed to any prior therapy for AML with the exception of:
-
Emergency leukapheresis and
-
Emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before the start of the trial treatment. Prior therapy for pre-existing hematological conditions, for example, MDS or MPD, including but not limited to hypomethylating agents, is also allowed until at least 2 weeks or 5 half-lives of that agent before the first dose of pimasertib
- Subjects meet at least one of the following conditions:
-
Age greater than or equal to 75 years OR
-
Age greater than or equal to 60 and less than 75 years with at least one of the following poor prognostic factors:
-
Secondary AML, as determined by known and documented exposure to leukemogenic therapy or environmental toxin or antecedent history of MDS or MPD according to WHO criteria for at least 3 months prior to trial entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting the diagnosis
-
At least one of the following unfavorable cytogenetic abnormalities: del(5q), -5, -7, del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (greater than or equal to 3 unrelated abnormalities)
-
Eastern Cooperative Oncology Group (ECOG) status 2
-
Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments
-
Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator such as two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age
Exclusion Criteria:
Part 1 and Part 2:
-
ECOG performance status 3 or greater
-
Hyperleukocytosis with greater than 30 x 10 to the ninth power per liter leukemia blasts in peripheral blood
-
Acute promyelocytic leukemia [t(15;17)]
-
Administration of any antineoplastic therapy within at least 2 weeks or 5 half lives of that therapy of the first pimasertib dose; except the use of hydroxyurea as permitted in inclusion criteria
-
Participation in other clinical trials within at least 2 weeks of the first pimasertib dose
-
Clinical evidence of active central nervous system leukemia
-
Active and uncontrolled infection including but not limited to known infection with human immunodeficiency virus (HIV), active hepatitis B or hepatitis C. Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry
-
Major surgery within two weeks prior to trial entry
-
Liver function tests above the following limits at screening: total bilirubin >1.5 x upper limit of normal (ULN) unless related to Gilbert's syndrome or hemolysis, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x ULN, or for subjects with liver involvement AST and/or ALT >5 x ULN
-
Serum creatinine >1.5 x ULN and /or creatinine clearance <30 milliliter per minute (mL/min) at screening
-
International normalized ratio (INR) greater than 1.5 x ULN unless on treatment with warfarin
-
For female subjects: pregnant or breast-feeding
-
History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product
-
Has significant cardiac conduction abnormalities and/or pacemaker
-
Has retinal degenerative disease (heredity retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion and/or any medically relevant abnormal findings at the initial ophthalmologic examination
-
Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrolment. Subjects with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study
-
Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
-
Other significant disease that in the Investigator's opinion would exclude the subject from the trial
-
Legal incapacity or limited legal capacity
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Northwestern University | Chicago | Illinois | United States | |
| 2 | Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Baltimore | Maryland | United States | |
| 3 | Beth Israel Deaconess Medical Center | Boston | Massachusetts | United States | |
| 4 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | |
| 5 | University of Texas - MD Anderson Cancer Center | Houston | Texas | United States | |
| 6 | Hospital Hotel Dieu, Service D'Hematologie | Nantes | Cedex | France | |
| 7 | Hospital Edouard Herriot, Service d'Hematologie Clinique | Lyon Cedex | France | ||
| 8 | Hospital Saint Louis, Service des Maladies du Sang | Paris | France | ||
| 9 | CHU du Haut-Leveque, Service des Maladies du Sang Unite de Recherche Clinique | Pessac | France |
Sponsors and Collaborators
- EMD Serono
Investigators
- Study Director: Medical responsible, Merck KGaA, Darmstadt, Germany
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
EMD Serono
ClinicalTrials.gov Identifier:
NCT00957580
Other Study ID Numbers:
- EMR200066_002
- 2009-010866-49
First Posted:
Aug 12, 2009
Last Update Posted:
Aug 21, 2017
Last Verified:
Jul 1, 2017
Keywords provided by EMD Serono
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | First/last subject (informed consent): September 2009/12 April 2012. Last subject completed : December 2012; Clinical data cut-off: December 2012. |
|---|---|
| Pre-assignment Detail | Enrolled: 116 screened for eligibility; 35 were excluded (mainly non-fulfillment of inclusion or exclusion). 81 subjects were randomized. |
| Arm/Group Title | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) |
|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Period Title: Overall Study | |||
| STARTED | 33 | 33 | 15 |
| Treated | 33 | 32 | 15 |
| COMPLETED | 33 | 31 | 15 |
| NOT COMPLETED | 0 | 2 | 0 |
Baseline Characteristics
| Arm/Group Title | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) | Total |
|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Total of all reporting groups |
| Overall Participants | 33 | 32 | 15 | 80 |
| Age, Customized (Subjects) [Number] | ||||
| 18 to less than (<) 60 |
14
|
12
|
6
|
32
|
| 60 to <75 |
13
|
16
|
6
|
35
|
| Greater than or equal to (>=) 75 |
6
|
4
|
3
|
13
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
9
27.3%
|
13
40.6%
|
7
46.7%
|
29
36.3%
|
| Male |
24
72.7%
|
19
59.4%
|
8
53.3%
|
51
63.8%
|
Outcome Measures
| Title | Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs) |
|---|---|
| Description | The DLT was any toxicity that resulted in treatment delay for more than (>) 2 weeks due to treatment-related adverse effects, or any Grade greater than or equal to (>=) 3 non-hematological toxicity excluding Grade 4 asymptomatic increases in liver function tests reversible within 7 days in subjects with liver involvement, and Grade 3 asymptomatic increases in liver function tests reversible within 7 days for subjects without liver involvement, Grade 3 vomiting unless encountered and persistent for more than 3 days despite adequate and optimal therapy, and Grade 3 diarrhea unless encountered and persistent for more than 3 days despite adequate and optimal anti-diarrhea therapy at any DL and judged to be possibly or probably related to the trial treatment by the Investigator and/or the Sponsor. |
| Time Frame | Baseline Up to Day 29 of Cycle 1 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The DLT analysis set included all subjects who received over 90 percent (%) administration of trial medication in Cycle 1 or showed a DLT. |
| Arm/Group Title | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) |
|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 21 | 22 | 13 |
| Number [subjects] |
1
|
0
|
5
|
| Title | Part 2: Percentage of Subjects With Best Overall Response |
|---|---|
| Description | The best overall response was to be reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) >1.0x10^9 per liter (/L), platelets >100x10^9 /L, bone marrow aspirate with less than or equal to (<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC >1.0x10^9/L, platelets >100x10^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (<) 5%. (4) Progressive disease (PD) = >50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = subjects who failed to achieve CR, CRi or PR and without criteria for PD. |
| Time Frame | Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Due to limited anti-leukemic effects observed in the safety run-in part decision was made not to conduct part 2 hence this outcome measure was not assessed. Effects observed in the safety run-in part decision was made not to conduct part 2 hence this outcome measure was not assessed. |
| Arm/Group Title | Regimen 1 (Part 2) | Regimen 2 (Part 2) |
|---|---|---|
| Arm/Group Description | Pimasertib was to be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was to be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 0 | 0 |
| Title | Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation |
|---|---|
| Description | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs include both SAEs and non-SAEs. |
| Time Frame | Baseline up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| The safety analysis set included all the subjects who received at least one administration of the trial medication. |
| Arm/Group Title | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) |
|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 33 | 32 | 15 |
| TEAEs |
33
|
32
|
15
|
| Serious TEAEs |
24
|
28
|
12
|
| TEAEs Leading to Death |
6
|
6
|
5
|
| TEAEs Leading to Treatment Discontinuation |
7
|
7
|
7
|
| Title | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose |
|---|---|
| Description | |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided adequate PK samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 6 | 9 | 7 | 9 | 4 | 19 | 10 | 4 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram/milliliter] |
14.8
(43.0)
|
29.3
(32.0)
|
59.1
(86.2)
|
132.8
(29.6)
|
151.6
(38.8)
|
207.0
(27.8)
|
269.9
(46.1)
|
241.9
(81.0)
|
342.6
(18.5)
|
| Title | Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose |
|---|---|
| Description | |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided adequate PK samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 11 | 10 | 8 | 9 | 13 | 2 | 16 | 5 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [nanogram/milliliter] |
23.6
(40.1)
|
59.3
(53.1)
|
69.6
(39.2)
|
150.1
(63.7)
|
187.8
(25.3)
|
123.2
(63.4)
|
231.4
(48.2)
|
383.2
(57.6)
|
486.3
(NA)
|
| Title | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose |
|---|---|
| Description | |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples per protocol. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 7 | 9 | 7 | 9 | 4 | 19 | 10 | 4 |
| Geometric Mean (Geometric Coefficient of Variation) [hour] |
0.94
(41.18)
|
2.25
(53.20)
|
1.56
(151.73)
|
1.09
(38.74)
|
1.11
(78.05)
|
1.12
(19.62)
|
1.03
(40.27)
|
2.70
(96.84)
|
1.17
(76.62)
|
| Title | Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose |
|---|---|
| Description | |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples per protocol. Number of subjects analysed refer to the subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 11 | 10 | 8 | 9 | 13 | 2 | 16 | 5 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [hour] |
1.44
(78.61)
|
1.75
(83.12)
|
2.03
(59.04)
|
1.99
(70.40)
|
1.64
(73.93)
|
1.41
(52.11)
|
1.78
(112.59)
|
2.75
(21.83)
|
2.00
(NA)
|
| Title | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose |
|---|---|
| Description | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 4 | 6 | 7 | 8 | 4 | 18 | 5 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [hour] |
5.28
(41.55)
|
3.52
(19.75)
|
3.05
(13.96)
|
4.01
(36.61)
|
3.88
(42.26)
|
3.45
(23.80)
|
2.97
(21.92)
|
4.21
(92.04)
|
3.39
(49.59)
|
| Title | Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose |
|---|---|
| Description | The apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 7 | 6 | 6 | 11 | 2 | 11 | 2 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [hour] |
6.97
(75.47)
|
10.91
(590.54)
|
3.69
(22.69)
|
3.93
(32.17)
|
3.71
(21.38)
|
3.96
(17.24)
|
4.52
(66.99)
|
8.44
(175.10)
|
5.04
(NA)
|
| Title | Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Single Dose |
|---|---|
| Description | |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 6 | 9 | 7 | 9 | 4 | 19 | 10 | 4 |
| Geometric Mean (Geometric Coefficient of Variation) [hour*nanogram/milliliter] |
54.0
(57.2)
|
125.4
(42.4)
|
230.9
(60.9)
|
456.2
(25.5)
|
581.8
(45.4)
|
735.2
(47.2)
|
863.8
(52.8)
|
905.0
(92.8)
|
1268.2
(31.9)
|
| Title | Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) of Pimasertib: Multiple Dose |
|---|---|
| Description | |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3). |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. '"n" =Subjects evaluable for this outcome measure for specified categories for each reporting group, respectively. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 11 | 10 | 8 | 9 | 13 | 2 | 16 | 5 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [hour*nanogram/milliliter] |
131.4
(45.5)
|
307.2
(75.4)
|
321.9
(29.9)
|
679.4
(53.7)
|
761.2
(35.5)
|
628.0
(28.2)
|
991.6
(66.1)
|
2195.2
(97.3)
|
2144.7
(NA)
|
| Title | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose |
|---|---|
| Description | The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity. |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 4 | 6 | 7 | 8 | 4 | 18 | 5 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [hour*nanogram/milliliter] |
80.5
(52.9)
|
145.2
(42.1)
|
315.6
(76.3)
|
562.1
(33.3)
|
734.9
(49.7)
|
858.4
(49.6)
|
1027.4
(49.2)
|
1530.7
(135.3)
|
1873.9
(68.8)
|
| Title | Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose |
|---|---|
| Description | The AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. It is obtained from AUC0-t plus AUCt-infinity. |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. N (number of subject analyzed) signifies subjects evaluable for this outcome measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 7 | 6 | 6 | 11 | 2 | 11 | 2 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [hour*nanogram/milliliter] |
226.2
(91.0)
|
789.3
(1038.0)
|
451.2
(39.4)
|
1030.2
(51.6)
|
938.0
(46.6)
|
786.7
(21.2)
|
1270.8
(104.3)
|
2712.6
(456.7)
|
2830.7
(NA)
|
| Title | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose |
|---|---|
| Description | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome. |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 4 | 6 | 7 | 8 | 4 | 18 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [liter/hour] |
99.43
(52.86)
|
103.29
(42.07)
|
72.88
(76.28)
|
53.37
(33.26)
|
57.15
(49.72)
|
52.42
(49.59)
|
58.40
(49.21)
|
48.03
(68.78)
|
| Title | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose |
|---|---|
| Description | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure and "n" = subjects evaluable for the specified regimen. |
| Arm/Group Title | Pimasertib 75 mg (All Regimens [Part 1]) |
|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 4 |
| Regimen 1 (n=0) |
NA
(NA)
|
| Regimen 2 (n=3) |
93
(103.367)
|
| Regimen 3 (n=1) |
45
(NA)
|
| Title | Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose |
|---|---|
| Description | Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Apparent clearance after oral dose (CL/f) is influenced by the fraction absorbed. |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 11 | 9 | 8 | 7 | 12 | 2 | 13 | 4 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [liter/hour] |
60.90
(45.51)
|
46.74
(78.85)
|
66.52
(33.40)
|
37.95
(47.59)
|
55.80
(35.90)
|
69.23
(33.40)
|
65.11
(65.69)
|
34.44
(119.51)
|
41.96
(NA)
|
| Title | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose |
|---|---|
| Description | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Data for Pimasertib 75 mg arm was not available for all the regimens combined, thus reported as separate outcome measure and not included in this outcome. |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 4 | 6 | 7 | 8 | 4 | 18 | 3 |
| Geometric Mean (Geometric Coefficient of Variation) [liter] |
757.5
(48.3)
|
524.8
(51.5)
|
320.8
(60.1)
|
308.8
(27.1)
|
320.2
(40.4)
|
260.8
(46.9)
|
250.3
(48.5)
|
235.2
(24.2)
|
| Title | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose |
|---|---|
| Description | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. |
| Time Frame | Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure and "n" = subjects evaluable for the specified regimen. |
| Arm/Group Title | Pimasertib 75 mg (All Regimens [Part 1]) |
|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 4 |
| Regimen 1 (n = 0) |
NA
(NA)
|
| Regimen 2 (n = 3) |
442.2
(214.6)
|
| Regimen 3 (n = 1) |
196.0
(NA)
|
| Title | Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose |
|---|---|
| Description | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. |
| Time Frame | Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set included all the subjects who received at least 1 dose of trial medication and provided pharmacokinetic samples. 'N'(number of subjects analyzed)=subjects evaluable for this measure. |
| Arm/Group Title | Pimasertib 8 mg (All Regimens [Part 1]) | Pimasertib 15 mg (All Regimens [Part 1]) | Pimasertib 23 mg (All Regimens [Part 1]) | Pimasertib 30 mg (All Regimens [Part 1]) | Pimasertib 42 mg (All Regimens [Part 1]) | Pimasertib 45 mg (All Regimens [Part 1]) | Pimasertib 60 mg (All Regimens [Part 1]) | Pimasertib 75 mg (All Regimens [Part 1]) | Pimasertib 90 mg (All Regimens [Part 1]) |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 15 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 23 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 30 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 42 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; and on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 45 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 75 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle in Regimen 1; on Days 1 to 21 of a 28-day cycle in Regimen 2; and on Days 1-28 of a 28-day cycle in Regimen 3. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 90 mg twice daily (BID) on Days 1 to 21 of a 28-day cycle in Regimen 2. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 9 | 7 | 6 | 6 | 11 | 2 | 11 | 2 | 1 |
| Geometric Mean (Geometric Coefficient of Variation) [liter] |
601.7
(79.2)
|
863.7
(193.5)
|
332.8
(14.5)
|
207.8
(46.8)
|
293.1
(27.6)
|
395.1
(52.9)
|
422.0
(79.2)
|
689.9
(16.0)
|
305.2
(NA)
|
| Title | Part 1: Percentage of Subjects With Best Overall Response |
|---|---|
| Description | The best overall response was reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) >1.0x10^9 per liter (/L), platelets >100x10^9 /L, bone marrow aspirate with less than or equal to (<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC >1.0x10^9/L, platelets >100x10^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (<) 5%. (4) Progressive disease (PD) = >50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = Subjects who failed to achieve CR, CRi or PR and without criteria for PD. |
| Time Frame | Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The efficacy analysis set included all subjects who received at least 1 administration of planned dose of pimasertib and had at least 1 efficacy assessment after the first dose. 'N' (number of subjects analyzed)=subjects evaluable for this outcome measure. |
| Arm/Group Title | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) |
|---|---|---|---|
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 20 | 22 | 7 |
| CR |
0.0
|
0.0
|
0.0
|
| CRi |
0.0
|
0.0
|
0.0
|
| PR |
0.0
|
0.0
|
0.0
|
| SD |
60.0
|
77.3
|
71.4
|
| PD |
40.0
|
22.7
|
28.6
|
| Title | Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation |
|---|---|
| Description | An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that results in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. |
| Time Frame | Up to 3 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| This outcome measure was not analyzed as the trial was terminated during safety run-in (Part 1). |
| Arm/Group Title | Regimen 1 (Part 2) | Regimen 2 (Part 2) |
|---|---|---|
| Arm/Group Description | Pimasertib was to be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was to be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose was to be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment was to be continued until disease progression, intolerable toxicity, or Investigator/subject decision. |
| Measure Participants | 0 | 0 |
Adverse Events
| Time Frame | Up to 3 years | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. SAEs and Other AEs (non-SAEs) were reported. | |||||
| Arm/Group Title | Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) | |||
| Arm/Group Description | Pimasertib was administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose was escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | Pimasertib was administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose was escalated to 75 mg BID until MTD was obtained. The treatment was continued until disease progression, intolerable toxicity, or Investigator/subject decision. | |||
All Cause Mortality |
||||||
| Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 24/33 (72.7%) | 28/32 (87.5%) | 12/15 (80%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Febrile Neutropenia | 4/33 (12.1%) | 9/32 (28.1%) | 2/15 (13.3%) | |||
| Neutropenia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Thrombocytopenia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Thrombocytosis | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Cardiac disorders | ||||||
| Acute coronary syndrome | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Atrial fibrillation | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Cardiac failure congestive | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Sinus bradycardia | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Eye disorders | ||||||
| Photopsia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Retinal detachment | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Visual impairment | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Caecitis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Colitis | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Diarrhoea | 2/33 (6.1%) | 2/32 (6.3%) | 2/15 (13.3%) | |||
| Gastrointestinal haemorrhage | 1/33 (3%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Ileus | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Large intestinal obstruction | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Lower gastrointestinal haemorrhage | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Mouth haemorrhage | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Nausea | 1/33 (3%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Stomatitis | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Toothache | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Upper gastrointestinal haemorrhage | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Vomiting | 1/33 (3%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| General disorders | ||||||
| Asthenia | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Disease progression | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Face oedema | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Fatigue | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| General physical health deterioration | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Mucosal inflammation | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Oedema peripheral | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Pyrexia | 1/33 (3%) | 5/32 (15.6%) | 1/15 (6.7%) | |||
| Infections and infestations | ||||||
| Bacteraemia | 2/33 (6.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Bronchopulmonary aspergillosis | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Cellulitis | 2/33 (6.1%) | 3/32 (9.4%) | 0/15 (0%) | |||
| Clostridial infection | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Clostridium difficile colitis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Device related infection | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Diverticulitis | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Enterococcal bacteraemia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Enterocolitis infectious | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Escherichia bacteraemia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Human herpes virus 6 infection | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Infection | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Influenza | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Lung Infection | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Parainfluenzae virus infection | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Pneumonia | 7/33 (21.2%) | 4/32 (12.5%) | 3/15 (20%) | |||
| Pneumonia fungal | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Sepsis | 2/33 (6.1%) | 3/32 (9.4%) | 1/15 (6.7%) | |||
| Septic shock | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Tonsillitis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Urinary tract infection | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Urinary tract infection enterococcal | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Hip fracture | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Overdose | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Subdural haematoma | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Asparatate aminotransferase increased | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Neutrophil count decreased | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| White Blood Cell Count Increased | 0/33 (0%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Dehydration | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Hyponatraemia | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Tumor lysis syndrome | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Nervous system disorders | ||||||
| Depressed level of consciousness | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Haemorrhage intracranial | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Subdural hygroma | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Syncope | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Psychiatric disorders | ||||||
| Delirium | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Renal and urinary disorders | ||||||
| Nephritic syndrome | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Renal failure | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Renal failure acute | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Renal tubular necrosis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Reproductive system and breast disorders | ||||||
| Cystocele | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute respiratory distress syndrome | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Acute respiratory failure | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Dyspnoea | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Epistaxis | 3/33 (9.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Hypoxia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Lung disorder | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Pleural Effusion | 1/33 (3%) | 0/32 (0%) | 2/15 (13.3%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Angioedema | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Rash maculo-papular | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Swelling face | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Vascular disorders | ||||||
| Deep vein thrombosis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Hypotension | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Shock haemorrhagic | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Varicose vein | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Regimen 1 (Part 1) | Regimen 2 (Part 1) | Regimen 3 (Part 1) | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 32/33 (97%) | 30/32 (93.8%) | 15/15 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 3/33 (9.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Febrile bone marrow aplasia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Febrile neutropenia | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Leukocytosis | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Lymphadenopathy | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Neutropenia | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Spontaneous haematoma | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Cardiac disorders | ||||||
| Atrial fibrillation | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Atrioventricular block second degree | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Bradycardia | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Pericardial effusion | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Pneumopericardium | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Sinus tachycardia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Tachycardia | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Ear and labyrinth disorders | ||||||
| Ear Pain | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Hypoacusis | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Vertigo | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Eye disorders | ||||||
| Blepharitis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Chorioretinopathy | 0/33 (0%) | 3/32 (9.4%) | 0/15 (0%) | |||
| Conjunctival hyperaemia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Conjunctival oedema | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Conjunctivitis | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Detachment of retinal pigment epithelium | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Dry eye | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Erythema of eyelid | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Eyelid disorder | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Eyelid oedema | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Lacrimation increased | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Macular Degeneration | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Macular oedema | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Metamorphopsia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Ocular hypertension | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Optic disc haemorrhage | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Periorbital oedema | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Photopsia | 0/33 (0%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Retinal detachment | 2/33 (6.1%) | 4/32 (12.5%) | 1/15 (6.7%) | |||
| Retinal haemorrhage | 0/33 (0%) | 0/32 (0%) | 2/15 (13.3%) | |||
| Retinal oedema | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Retinal vein occlusion | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Scotoma | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Vision blurred | 4/33 (12.1%) | 5/32 (15.6%) | 1/15 (6.7%) | |||
| Visual acuity reduced | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Visual impairment | 0/33 (0%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Vitreous floaters | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Xerophthalmia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal distension | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Abdominal pain | 4/33 (12.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Abdominal pain upper | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Anal fissure | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Aphthous stomatitis | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Constipation | 3/33 (9.1%) | 3/32 (9.4%) | 1/15 (6.7%) | |||
| Diarrhoea | 14/33 (42.4%) | 16/32 (50%) | 8/15 (53.3%) | |||
| Dry mouth | 2/33 (6.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Dysphagia | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Faecal incontinence | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Flatulence | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Gastrooesophageal reflux disease | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Gingival bleeding | 1/33 (3%) | 2/32 (6.3%) | 1/15 (6.7%) | |||
| Gingival inflammation | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Haematemesis | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Hyperchlorhydria | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Lip oedema | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Melaena | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Mouth haemorrhage | 4/33 (12.1%) | 2/32 (6.3%) | 1/15 (6.7%) | |||
| Mouth ulceration | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Nausea | 10/33 (30.3%) | 7/32 (21.9%) | 2/15 (13.3%) | |||
| Oral disorder | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Oral pain | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Proctalgia | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Rectal haemorrhage | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Stomatitis | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Stomatitis necrotising | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Vomiting | 6/33 (18.2%) | 6/32 (18.8%) | 1/15 (6.7%) | |||
| General disorders | ||||||
| Asthenia | 4/33 (12.1%) | 5/32 (15.6%) | 2/15 (13.3%) | |||
| Chest pain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Chills | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Face oedema | 0/33 (0%) | 1/32 (3.1%) | 2/15 (13.3%) | |||
| Fatigue | 5/33 (15.2%) | 5/32 (15.6%) | 2/15 (13.3%) | |||
| Generalised oedema | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Hyperthermia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Influenza like illness | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Localised oedema | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Malaise | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Mucosal inflammation | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Oedema | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Oedema peripheral | 6/33 (18.2%) | 8/32 (25%) | 4/15 (26.7%) | |||
| Pyrexia | 7/33 (21.2%) | 8/32 (25%) | 1/15 (6.7%) | |||
| Infusion site oedema | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Hepatobiliary disorders | ||||||
| Hyperbilirubinaemia | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Immune system disorders | ||||||
| Graft versus host disease in intestine | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Graft versus host disease in skin | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Infections and infestations | ||||||
| Anal abscess | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Bacteraemia | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Bronchitis | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Cellulitis | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Clostridial infection | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Gastroenteritis | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Herpes simplex ophthalmic | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Human herpesvirus 6 virus infection | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Localised infection | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Nasopharyngitis | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Oral candidiasis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Oral fungal infection | 0/33 (0%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Paronychia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Pneumonia | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Rhinitis | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Sepsis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Sinusitis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Staphylococcal sepsis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Upper respiratory tract infection | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Urinary tract infection | 2/33 (6.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Hordeolum | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Contusion | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Craniocerebral injury | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Eschar | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Muscle strain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Overdose | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Procedural pain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Subdural haematoma | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Transfusion reaction | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Wound | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Investigations | ||||||
| Activated partial thromboplastin time prolonged | 3/33 (9.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Alanine aminotransferase increased | 6/33 (18.2%) | 4/32 (12.5%) | 1/15 (6.7%) | |||
| Aspartate aminotransferase increased | 8/33 (24.2%) | 7/32 (21.9%) | 3/15 (20%) | |||
| Blood albumin decreased | 4/33 (12.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Blood alkaline phosphatase increased | 5/33 (15.2%) | 3/32 (9.4%) | 2/15 (13.3%) | |||
| Blood bilirubin increased | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Blood calcium decreased | 4/33 (12.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Blood creatine increased | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Blood creatinine | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Blood creatinine increased | 0/33 (0%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Blood glucose increased | 2/33 (6.1%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Blood magnesium decreased | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Blood phosphorus increased | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Blood potassium decreased | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Blood sodium decreased | 4/33 (12.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Blood urea increased | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Blood uric acid increased | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Electrocardiogram QT prolonged | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Gamma-glutamyltransferase | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Gamma-glutamyltransferase increased | 3/33 (9.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Haemoglobin decreased | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| International normalised ratio increased | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Neutrophil count decreased | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Weight decreased | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Weight increased | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Metabolism and nutrition disorders | ||||||
| Decreased appetite | 0/33 (0%) | 3/32 (9.4%) | 1/15 (6.7%) | |||
| Dehydration | 0/33 (0%) | 2/32 (6.3%) | 2/15 (13.3%) | |||
| Hyperglycaemia | 3/33 (9.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Hyperkalaemia | 2/33 (6.1%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Hypermagnesaemia | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Hypernatraemia | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Hyperphosphataemia | 1/33 (3%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Hyperuricaemia | 2/33 (6.1%) | 3/32 (9.4%) | 3/15 (20%) | |||
| Hypoalbuminaemia | 1/33 (3%) | 2/32 (6.3%) | 3/15 (20%) | |||
| Hypocalcaemia | 1/33 (3%) | 2/32 (6.3%) | 4/15 (26.7%) | |||
| Hypoglycaemia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Hypokalaemia | 3/33 (9.1%) | 5/32 (15.6%) | 1/15 (6.7%) | |||
| Hypomagnesaemia | 0/33 (0%) | 3/32 (9.4%) | 0/15 (0%) | |||
| Hyponatraemia | 2/33 (6.1%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Hypophosphataemia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Malnutrition | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Metabolic acidosis | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Back pain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Hypercreatinaemia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Muscle spasms | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Muscular weakness | 0/33 (0%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Musculoskeletal chest pain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Musculoskeletal pain | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Pain in extremity | 4/33 (12.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Synovial cyst | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Benign neoplasm of skin | 0/33 (0%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Nervous system disorders | ||||||
| Aphonia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Cognitive disorder | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Convulsion | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Dizziness | 7/33 (21.2%) | 5/32 (15.6%) | 2/15 (13.3%) | |||
| Dysgeusia | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Headache | 3/33 (9.1%) | 6/32 (18.8%) | 1/15 (6.7%) | |||
| Hypoaesthesia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Hypokinesia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Lethargy | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Neuropathy peripheral | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Paraesthesia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Sciatica | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Somnolence | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Syncope | 2/33 (6.1%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Psychiatric disorders | ||||||
| Agitation | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Anxiety | 3/33 (9.1%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Confusional state | 3/33 (9.1%) | 3/32 (9.4%) | 0/15 (0%) | |||
| Hallucination | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Hallucination, visual | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Insomnia | 1/33 (3%) | 2/32 (6.3%) | 1/15 (6.7%) | |||
| Renal and urinary disorders | ||||||
| Dysuria | 2/33 (6.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Haematuria | 2/33 (6.1%) | 0/32 (0%) | 0/15 (0%) | |||
| Pollakiuria | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Proteinuria | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Renal failure acute | 2/33 (6.1%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Reproductive system and breast disorders | ||||||
| Testis discomfort | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Uterine prolapse | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Vulvovaginal pain | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute pulmonary oedema | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Acute respiratory distress syndrome | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Acute respiratory failure | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Cough | 5/33 (15.2%) | 3/32 (9.4%) | 0/15 (0%) | |||
| Dysphonia | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Dyspnoea | 2/33 (6.1%) | 2/32 (6.3%) | 2/15 (13.3%) | |||
| Dyspnoea exertional | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Epistaxis | 5/33 (15.2%) | 5/32 (15.6%) | 0/15 (0%) | |||
| Nasal congestion | 0/33 (0%) | 0/32 (0%) | 2/15 (13.3%) | |||
| Oropharyngeal pain | 1/33 (3%) | 2/32 (6.3%) | 0/15 (0%) | |||
| Pleural effusion | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Productive cough | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Respiratory failure | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Rhinorrhoea | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Tachypnoea | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Wheezing | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Acne | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Alopecia | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Blood blister | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Decubitus ulcer | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Dermatitis acneiform | 1/33 (3%) | 1/32 (3.1%) | 1/15 (6.7%) | |||
| Dermatitis diaper | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Dry skin | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Erythema | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Exfoliative rash | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Hyperhidrosis | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Petechiae | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Pruritus | 2/33 (6.1%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Purpura | 1/33 (3%) | 1/32 (3.1%) | 0/15 (0%) | |||
| Rash | 4/33 (12.1%) | 6/32 (18.8%) | 4/15 (26.7%) | |||
| Rash generalised | 1/33 (3%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Rash macular | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Rash maculo-papular | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Skin disorder | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Skin lesion | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Skin reaction | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Swelling face | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Vascular disorders | ||||||
| Deep vein thrombosis | 0/33 (0%) | 0/32 (0%) | 1/15 (6.7%) | |||
| Flushing | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Hot flush | 1/33 (3%) | 0/32 (0%) | 0/15 (0%) | |||
| Hypertension | 1/33 (3%) | 2/32 (6.3%) | 1/15 (6.7%) | |||
| Hypotension | 4/33 (12.1%) | 6/32 (18.8%) | 1/15 (6.7%) | |||
| Orthostatic hypotension | 0/33 (0%) | 1/32 (3.1%) | 0/15 (0%) | |||
Limitations/Caveats
The trial has been terminated due to an estimated low probability of clinical benefit based on limited anti-leukemic effects observed in safety run-in (Part 1).
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Results Point of Contact
| Name/Title | Merck KGaA Communication Center |
|---|---|
| Organization | Merck Serono, a division of Merck KGaA |
| Phone | +49-6151-72-5200 |
| service@merckgroup.com |
Responsible Party:
EMD Serono
ClinicalTrials.gov Identifier:
NCT00957580
Other Study ID Numbers:
- EMR200066_002
- 2009-010866-49
First Posted:
Aug 12, 2009
Last Update Posted:
Aug 21, 2017
Last Verified:
Jul 1, 2017