A Phase 1b/2 Study of IPI-145 Plus FCR in Previously Untreated, Younger Patients With CLL
Study Details
Study Description
Brief Summary
This research study is evaluating a new drug called IPI-145 in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR), as a possible treatment for chronic lymphocytic leukemia (CLL).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
Patients who fulfill eligibility criteria will be entered into the trial to receive IPI-145 in combination with the standard drugs fludarabine, cyclophosphamide, and rituximab (FCR).
After the screening procedures confirm participation in the research study:
Phase I
The investigators are looking for the highest dose of the combination of study drugs that can be administered safely without severe or unmanageable side effects in participants that have CLL. Not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study prior and how well the dose was tolerated.
Phase II:
Patients treated with IPI-145 at the Recommended Phase II Dose (RP2D) + fludarabine, cyclophosphamide, rituximab (FCR) with standard dosing.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: IPI-145 Phase I-Dose escalation will occur using a standard 3-3 dose escalation beginning in dose level 1 with dose cohorts and escalation. Each treatment cycle lasts 28 days (except cycle 1, which is 35 days) during which time IPI-145 will be taken twice daily. The study begins with 1 week of IPI-145 monotherapy. Fludarabine, cyclophosphamide, rituximab (iFCR) - FCR will subsequently be introduced after 1 week and administered at standard dosing for up to 6 cycles, with dose reductions permitted. IPI-145 will be continued through the course of chemotherapy and for up to 2 years maintenance after completing chemotherapy Phase II - 20 additional patients treated with IPI-145 at the Recommended Phase II Dose (RP2D) + fludarabine, cyclophosphamide, rituximab (FCR) with standard dosing. |
Drug: IPI-145
oral PI3K delta/gamma inhibitor
Drug: Fludarabine
intravenous chemotherapy
Other Names:
Drug: Cyclophosphamide
intravenous chemotherapy
Other Names:
Drug: Rituximab
intravenous immunotherapy
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I [. Participants were assessed every week or more often as needed during Cycle 1, and every Day 1 Cycles 2 and onward-Dose-limiting toxicities (DLTs) occurring during the first cycle of treatment will be used in determining the Phase II MTD/RP2D]
To assess the safety of IPI145 in combination with FCR in previously untreated younger patients with CLL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 3 or greater hematologic toxicity (except Grade 3 or Grade 4 neutropenia or thrombocytopenia that lasts less than or equal to 10 days off treatment), any Grade 3 or greater non-hematologic toxicity (except Grade 3 or greater nausea, vomiting, diarrhea, Grade 3 infusion reactions), Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 3 days, Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to drug related toxicity from prior cycle, and any Grade 4 or greater elevation in AST ALT values
- Number of Patients Who Had a Minimal Residual Disease (MRD) Negative Complete Response (CR) 2 Months After Chemotherapy [2 months after completion of combination therapy of IPI-145 and FCR]
To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 2 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (IPI-145+ FCR) in tandem with a chest,neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. This will include all patients treated and evaluable at maximum tolerated dose, and at the recommended phase II dose ( RP2D)
Secondary Outcome Measures
- Overall Response Rate [At baseline, End of Cycle 3, and 2 months post FCR]
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
- Number of Participants With Serious and Non-Serious Adverse Events [Up to 210 days]
Toxicity assessments will be done using the CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) and will include all participants who have received at least 1 dose of IPI-145. Toxicities will be assessed at minimum every week during cycle 1, on Day 1 of every cycle during Cycle 2 onward, and every other cycle Day 1 during maintenance.
- Rate of Minimal Residual Disease (MRD) in the Peripheral Blood [2 Years]
Participants will have MRD testing in the peripheral blood by four-color flow cytometry at the end of cycle 3, 2 months post combination therapy, and every 6 months thereafter for the duration of treatment and subsequent follow up
- Rate of Treatment Related Adverse Effects [210 days]
Participants will be evaluable for this endpoint if they have had at least 1 dose of study treatment. Toxicities will be assessed at minimum each week during cycle 1, and each day 1 during combination therapy, and then every two months thereafter. CTCAE version 4.0 will be used to assess toxicity term and grading.
- Determine the Association of Established CLL Prognostic Factors With Clinical Response [2 Years]
Fisher's exact test for categorical variables and Wilcoxon's rank sum test will be used-
- Rate of Complete Response and Partial Response [At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter]
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
- Rate of Progression Free Survival [At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter]
2008 IW-CLL criteria
- Event Free Survival Rate [At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter]
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)
- Duration of Remission Rate [At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter]
Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)Frequency of follow up visits and scans are per MD discretion. Recommended follow up visits for a minimum of one year
Eligibility Criteria
Criteria
Inclusion Criteria:
-
confirmed diagnosis of CLL and an indication for treatment as per IW-CLL 2008 criteria
-
no prior therapy for CLL
-
age 18-65 -- ECOG performance status ≤1
Exclusion Criteria:
-
May not be receiving any other study agents
-
Known CNS involvement
-
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
-
Pregnant women are excluded from this study because IPI-145 has the potential for teratogenic or abortifacient effects.
-
Individuals with a history of a different malignancy are ineligible except for the following circumstances. disease-free for at least 5 years and deemed to be at low risk for recurrence. Individuals with the following cancers are eligible if diagnosed and treated with curative intent within the past 5 years: cervical cancer in situ, localized prostate cancer, and basal cell or squamous cell carcinoma of the skin
-
HIV-positive individuals, because of the potential for pharmacokinetic interactions with IPI-145
-
Inadequate hepatic function defined by aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x upper limit of normal (ULN); direct bilirubin >1.5 x ULN, unless due to hemolysis or Gilbert's syndrome
-
Inadequate renal function defined by serum creatinine >1.5 x ULN.
-
Baseline QTcF >480 ms. NOTE: This criterion does not apply to patients with a left bundle branch block
-
Concurrent treatment with any agent known to prolong the QTc interval
-
Patients with a history of active tuberculosis within the preceding two years.
-
Patients who have had a venous thromboembolic event (e.g., PE/DVT) requiring anticoagulation and who meet any of the following criteria:
-
Have been on a stable dose of anticoagulation for <1 month
-
Have had a Grade 2, 3 or 4 hemorrhage in the last 30 days
-
Are experiencing continued symptoms from their event
-
History of alcohol abuse, chronic hepatitis, or other chronic liver disease (other than direct CLL liver involvement)
-
Foods or medications that are strong or moderate inhibitors or inducers of CYP3A taken within 1 week prior to study treatment and for the duration of the study
-
Unable to receive prophylactic treatment for pneumocystis
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Beth Isreal Deaconess Medical Center | Boston | Massachusetts | United States | 02115 |
| 2 | Dana Farber Cancer Institute | Boston | Massachusetts | United States | 02115 |
Sponsors and Collaborators
- Dana-Farber Cancer Institute
- Verastem, Inc.
Investigators
- Principal Investigator: Matthew Davids, MD, Dana-Farber Cancer Institute
Study Documents (Full-Text)
More Information
Publications
None provided.- 14-193
Study Results
Participant Flow
| Recruitment Details | Participants in the Phase I portion of the study enrolled in outpatient clinic setting from 6/27/2014 to 1/13/2015 and to the Phase II study from 4/14/2015 to 8/15/2016 |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Phase I Cohort 1: IPI-145 25mg Once Daily + FCR | Phase I Cohort 2 (MTD): IPI-145 25mg Twice Daily + FCR | Phase II Dose Expansion(RP2D)-IPI-145 25mg Twice Daily + FCR |
|---|---|---|---|
| Arm/Group Description | Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase I Cohort 2 patients received oral agent IPI-145 25mg twice daily ( BID)on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase II (MTD)CLL participants received the regimen established in the Phase I study ( January 2015). Phase II Participants received oral IPI-145 25mg twice daily (BID) for up to 6 cycles of combination therapy and 2 years of maintenance ( monotherapy) and received standard dosing if Fludarabine, Cyclophosphamide, and Rituxan (FCR) on days 1-3 of each cycle for up to 6 cycles. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. |
| Period Title: Overall Study | |||
| STARTED | 6 | 6 | 20 |
| COMPLETED | 4 | 5 | 20 |
| NOT COMPLETED | 2 | 1 | 0 |
Baseline Characteristics
| Arm/Group Title | Phase I Cohort 1: IPI-145 25mg Once Daily + FCR | Phase I Cohort 2: IPI-145 25mg Once Daily | Phase II Dose Expansion ( MTD): IPI 145 25mg BID | Total |
|---|---|---|---|---|
| Arm/Group Description | Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase I Cohort 2 patients received oral agent IPI-145 25mg twice BID) daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase II (MTD) CLL participants received the regimen established in the Phase I study ( January 2015). Phase II Participants received oral IPI-145 25mg twice daily (BID) for up to 6 cycles of combination therapy and 2 years of maintenance ( monotherapy) and received standard dosing if Fludarabine, Cyclophosphamide, and Rituxan (FCR) on days 1-3 of each cycle for up to 6 cycles. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Total of all reporting groups |
| Overall Participants | 6 | 6 | 20 | 32 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
6
100%
|
5
83.3%
|
20
100%
|
31
96.9%
|
| >=65 years |
0
0%
|
1
16.7%
|
0
0%
|
1
3.1%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
1
16.7%
|
3
50%
|
6
30%
|
10
31.3%
|
| Male |
5
83.3%
|
3
50%
|
14
70%
|
22
68.8%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
1
16.7%
|
1
5%
|
2
6.3%
|
| Not Hispanic or Latino |
6
100%
|
5
83.3%
|
17
85%
|
28
87.5%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
2
10%
|
2
6.3%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
6
100%
|
6
100%
|
18
90%
|
30
93.8%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
2
10%
|
2
6.3%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
6
100%
|
6
100%
|
20
100%
|
32
100%
|
Outcome Measures
| Title | Number of Patients Who Experienced a Dose Limiting Toxicity (DLT) During Phase I |
|---|---|
| Description | To assess the safety of IPI145 in combination with FCR in previously untreated younger patients with CLL. DLT is based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. DLT refers to toxicities experienced at any time during the study treatment, defined as Grade 3 or greater hematologic toxicity (except Grade 3 or Grade 4 neutropenia or thrombocytopenia that lasts less than or equal to 10 days off treatment), any Grade 3 or greater non-hematologic toxicity (except Grade 3 or greater nausea, vomiting, diarrhea, Grade 3 infusion reactions), Grade 3 asymptomatic laboratory abnormalities that improve to grade 2 or less within 3 days, Inability to receive day 1 therapy of Cycle 2 even after a three week treatment delay due to drug related toxicity from prior cycle, and any Grade 4 or greater elevation in AST ALT values |
| Time Frame | . Participants were assessed every week or more often as needed during Cycle 1, and every Day 1 Cycles 2 and onward-Dose-limiting toxicities (DLTs) occurring during the first cycle of treatment will be used in determining the Phase II MTD/RP2D |
Outcome Measure Data
| Analysis Population Description |
|---|
| Patients who have received no prior therapy for CLL but who meet IW-CLL 2008 Criteria for requiring treatment |
| Arm/Group Title | Phase I Cohort 1: IPI-145 25mg Once Daily + FCR | Phase I Cohort 2 (MTD): IPI-145 25mg Twice Daily + FCR |
|---|---|---|
| Arm/Group Description | Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase I Cohort 2 patients received oral agent IPI-145 25mg twice daily ( BID)on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. |
| Measure Participants | 6 | 6 |
| Count of Participants [Participants] |
2
33.3%
|
1
16.7%
|
| Title | Number of Patients Who Had a Minimal Residual Disease (MRD) Negative Complete Response (CR) 2 Months After Chemotherapy |
|---|---|
| Description | To determine the rate of minimal residual disease negative complete response (MRD negative CR) in the bone marrow at 2 months post last cycle of FCR, participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (IPI-145+ FCR) in tandem with a chest,neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4. This will include all patients treated and evaluable at maximum tolerated dose, and at the recommended phase II dose ( RP2D) |
| Time Frame | 2 months after completion of combination therapy of IPI-145 and FCR |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Phase I MTD and Phase II RP2D: IPI 145 25 mg BID + FCR |
|---|---|
| Arm/Group Description | Phase I Cohort 2 (MTD) patients and Dose Expansion patients (RP2D) received oral agent IPI-145 25mg twice daily (BID)on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. |
| Measure Participants | 26 |
| Number (95% Confidence Interval) [Percentage of participants] |
23
383.3%
|
| Title | Overall Response Rate |
|---|---|
| Description | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) |
| Time Frame | At baseline, End of Cycle 3, and 2 months post FCR |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Number of Participants With Serious and Non-Serious Adverse Events |
|---|---|
| Description | Toxicity assessments will be done using the CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events (CTCAE) and will include all participants who have received at least 1 dose of IPI-145. Toxicities will be assessed at minimum every week during cycle 1, on Day 1 of every cycle during Cycle 2 onward, and every other cycle Day 1 during maintenance. |
| Time Frame | Up to 210 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Rate of Minimal Residual Disease (MRD) in the Peripheral Blood |
|---|---|
| Description | Participants will have MRD testing in the peripheral blood by four-color flow cytometry at the end of cycle 3, 2 months post combination therapy, and every 6 months thereafter for the duration of treatment and subsequent follow up |
| Time Frame | 2 Years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Rate of Treatment Related Adverse Effects |
|---|---|
| Description | Participants will be evaluable for this endpoint if they have had at least 1 dose of study treatment. Toxicities will be assessed at minimum each week during cycle 1, and each day 1 during combination therapy, and then every two months thereafter. CTCAE version 4.0 will be used to assess toxicity term and grading. |
| Time Frame | 210 days |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Determine the Association of Established CLL Prognostic Factors With Clinical Response |
|---|---|
| Description | Fisher's exact test for categorical variables and Wilcoxon's rank sum test will be used- |
| Time Frame | 2 Years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Rate of Complete Response and Partial Response |
|---|---|
| Description | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) |
| Time Frame | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Rate of Progression Free Survival |
|---|---|
| Description | 2008 IW-CLL criteria |
| Time Frame | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Event Free Survival Rate |
|---|---|
| Description | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008) |
| Time Frame | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
| Title | Duration of Remission Rate |
|---|---|
| Description | Response and progression will be evaluated in this study using the 2008 IW-CLL criteria for CLL (Hallek et al., 2008)Frequency of follow up visits and scans are per MD discretion. Recommended follow up visits for a minimum of one year |
| Time Frame | At baseline, End of Cycle 3, and 2 months post FCR and then per investigator discretion thereafter |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | Adverse events are assessed at minimum every week during cycle 1, and day 1 of every cycle thereafter during combination, and every two cycles thereafter while in maintenance. Treatment duration in cycles was a a median of 6 cycles in Phase I Cohort 1, 4.5 cycles in Phase I Cohort 2 and 5.5 cycles in the Phase II MTD | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Maximum grade toxicity by type-Serious AEs were defined as per DFCI criteria: Any grade 2 or 3 unexpected and treatment related event, and all grade 4 and 5 events regardless of attribution to study treatment, and includes events deemed medically important by overall PI. Other AEs were defined as events with the attribution of at least possibly related to the study treatment that did not meet the SAE criteria. CTCAE 4.0 was used in investigator assessment and lab value review. | |||||
| Arm/Group Title | Phase 1 Cohort 1: IPI-145 25mg Once Daily + FCR | Phase 1 Cohort 2: IPI-145 25mg Twice Daily + FCR | Phase II Dose Expansion(MTD)-IPI-145 25mg Twice Daily + FCR | |||
| Arm/Group Description | Phase I Cohort 1 patients received oral agent IPI-145 25mg daily on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase I Cohort 2 patients received oral agent IPI-145 25mg twice daily ( BID)on days 1-28 of a 28 day cycle, except for Cycle 1, which lasts 35 with a 7 day IPI-145 run in, then will continue daily dosing for 6 cycles and up to 2 years of maintenance. Fludarabine, cyclophosphamide, rituximab (FCR) swill be given standard dosing intravenously (IV) Days 1-3 during week 1 of a cycle for up to 6 cycles, with dose reductions permitted. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | Phase II (MTD)CLL participants received the regimen established in the Phase I study ( January 2015). Phase II Participants received oral IPI-145 25mg twice daily (BID) for up to 6 cycles of combination therapy and 2 years of maintenance ( monotherapy) and received standard dosing if Fludarabine, Cyclophosphamide, and Rituxan (FCR) on days 1-3 of each cycle for up to 6 cycles. Patients are treated until progression without clinical benefit, toxicity, or withdrawal of consent by the patient, or closure of the trial by the Overall PI or regulatory authorities. | |||
All Cause Mortality |
||||||
| Phase 1 Cohort 1: IPI-145 25mg Once Daily + FCR | Phase 1 Cohort 2: IPI-145 25mg Twice Daily + FCR | Phase II Dose Expansion(MTD)-IPI-145 25mg Twice Daily + FCR | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/6 (0%) | 0/20 (0%) | |||
Serious Adverse Events |
||||||
| Phase 1 Cohort 1: IPI-145 25mg Once Daily + FCR | Phase 1 Cohort 2: IPI-145 25mg Twice Daily + FCR | Phase II Dose Expansion(MTD)-IPI-145 25mg Twice Daily + FCR | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 6/6 (100%) | 20/20 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Febrile neutropenia | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 1 | 2/20 (10%) | 2 |
| Cardiac disorders | ||||||
| Pericarditis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Gastrointestinal disorders | ||||||
| Colitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 4/20 (20%) | 4 |
| Hepatobiliary disorders | ||||||
| Drug Induced Liver Injury | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Pancreatitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Blood Bilirubin Increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Immune system disorders | ||||||
| Inflammatory Bursitis | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Pityriasis Rubra Pilaris Reaction | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Infections and infestations | ||||||
| Sinusitis | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/20 (0%) | 0 |
| Investigations | ||||||
| Thrombocytopenia | 1/6 (16.7%) | 1 | 3/6 (50%) | 3 | 5/20 (25%) | 5 |
| Leukopenia | 3/6 (50%) | 3 | 3/6 (50%) | 3 | 4/20 (20%) | 4 |
| Neutrophil Count Decrease | 5/6 (83.3%) | 5 | 4/6 (66.7%) | 4 | 10/20 (50%) | 10 |
| Lymphopenia | 5/6 (83.3%) | 5 | 4/6 (66.7%) | 4 | 5/20 (25%) | 5 |
| Lipase Increased | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 1/20 (5%) | 1 |
| Alanine Aminotransferase Increased | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 3/20 (15%) | 3 |
| Aspartate Aminotransferase Increased | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 3/20 (15%) | 3 |
| Alkaline Phosphatase Increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Amylase Increased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Metabolism and nutrition disorders | ||||||
| Dehydration | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/20 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Neck Stiffness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/20 (5%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Myelodysplastic Syndrome | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/20 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Lung Infection | 2/6 (33.3%) | 2 | 2/6 (33.3%) | 2 | 1/20 (5%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Phase 1 Cohort 1: IPI-145 25mg Once Daily + FCR | Phase 1 Cohort 2: IPI-145 25mg Twice Daily + FCR | Phase II Dose Expansion(MTD)-IPI-145 25mg Twice Daily + FCR | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/6 (100%) | 6/6 (100%) | 20/20 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Anemia | 3/6 (50%) | 2/6 (33.3%) | 7/20 (35%) | |||
| Edema limbs | 1/6 (16.7%) | 1/6 (16.7%) | 2/20 (10%) | |||
| Febrile neutropenia | 1/6 (16.7%) | 1/6 (16.7%) | 2/20 (10%) | |||
| Leukocytosis | 0/6 (0%) | 0/6 (0%) | 2/20 (10%) | |||
| Cardiac disorders | ||||||
| Cardiac disorders - Other, specify | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Tinnitus | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Eye disorders | ||||||
| Blurred vision | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Eye disorders - Other, specify | 0/6 (0%) | 2/6 (33.3%) | 1/20 (5%) | |||
| Eye pain | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Gastrointestinal disorders | ||||||
| Abdominal pain | 1/6 (16.7%) | 0/6 (0%) | 3/20 (15%) | |||
| Bloating | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Colitis | 0/6 (0%) | 0/6 (0%) | 2/20 (10%) | |||
| Constipation | 5/6 (83.3%) | 2/6 (33.3%) | 2/20 (10%) | |||
| Diarrhea | 4/6 (66.7%) | 2/6 (33.3%) | 9/20 (45%) | |||
| Dry mouth | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Dyspepsia | 0/6 (0%) | 0/6 (0%) | 2/20 (10%) | |||
| Esophageal pain | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Gastroesophageal reflux disease | 0/6 (0%) | 1/6 (16.7%) | 2/20 (10%) | |||
| Gastrointestinal disorders - Other, specify | 4/6 (66.7%) | 2/6 (33.3%) | 4/20 (20%) | |||
| Mucositis oral | 1/6 (16.7%) | 0/6 (0%) | 1/20 (5%) | |||
| Nausea | 6/6 (100%) | 5/6 (83.3%) | 12/20 (60%) | |||
| Oral pain | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Stomach pain | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Tooth discoloration | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Vomiting | 4/6 (66.7%) | 1/6 (16.7%) | 4/20 (20%) | |||
| General disorders | ||||||
| Fatigue | 6/6 (100%) | 6/6 (100%) | 10/20 (50%) | |||
| General disorders and administration site conditions - Other, specify | 3/6 (50%) | 0/6 (0%) | 3/20 (15%) | |||
| Malaise | 1/6 (16.7%) | 0/6 (0%) | 2/20 (10%) | |||
| Pain | 1/6 (16.7%) | 1/6 (16.7%) | 2/20 (10%) | |||
| Immune system disorders | ||||||
| Fever | 4/6 (66.7%) | 4/6 (66.7%) | 9/20 (45%) | |||
| Flu like symptoms | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Infections and infestations | ||||||
| Infections and infestations - Other, specify | 2/6 (33.3%) | 0/6 (0%) | 1/20 (5%) | |||
| Lung infection | 0/6 (0%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Upper respiratory infection | 3/6 (50%) | 2/6 (33.3%) | 2/20 (10%) | |||
| Urinary tract infection | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Vaginal infection | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Wound infection | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Injury, poisoning and procedural complications | ||||||
| Bruising | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Injury, poisoning and procedural complications - Other, specify | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Investigations | ||||||
| Alanine aminotransferase increased | 2/6 (33.3%) | 1/6 (16.7%) | 8/20 (40%) | |||
| Alkaline phosphatase increased | 0/6 (0%) | 1/6 (16.7%) | 3/20 (15%) | |||
| Aspartate aminotransferase increased | 2/6 (33.3%) | 1/6 (16.7%) | 7/20 (35%) | |||
| Blood bilirubin increased | 0/6 (0%) | 0/6 (0%) | 2/20 (10%) | |||
| Investigations - Other, specify | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Lipase increased | 0/6 (0%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Lymphocyte count decreased | 3/6 (50%) | 2/6 (33.3%) | 4/20 (20%) | |||
| Lymphocyte count increased | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Neutrophil count decreased | 5/6 (83.3%) | 3/6 (50%) | 9/20 (45%) | |||
| Platelet count decreased | 6/6 (100%) | 2/6 (33.3%) | 10/20 (50%) | |||
| Serum amylase increased | 0/6 (0%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Weight gain | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Weight loss | 2/6 (33.3%) | 1/6 (16.7%) | 0/20 (0%) | |||
| White blood cell decreased | 6/6 (100%) | 4/6 (66.7%) | 4/20 (20%) | |||
| Metabolism and nutrition disorders | ||||||
| Anorexia | 5/6 (83.3%) | 3/6 (50%) | 3/20 (15%) | |||
| Dehydration | 2/6 (33.3%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Hyperglycemia | 2/6 (33.3%) | 0/6 (0%) | 0/20 (0%) | |||
| Hyperuricemia | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Hypoalbuminemia | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Hypoglycemia | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Hypophosphatemia | 1/6 (16.7%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 0/6 (0%) | 0/6 (0%) | 2/20 (10%) | |||
| Back pain | 2/6 (33.3%) | 0/6 (0%) | 1/20 (5%) | |||
| Bone pain | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Flank pain | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Generalized muscle weakness | 2/6 (33.3%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Muscle weakness lower limb | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Musculoskeletal and connective tissue disorder - Other, specify | 2/6 (33.3%) | 4/6 (66.7%) | 2/20 (10%) | |||
| Myalgia | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Non-cardiac chest pain | 1/6 (16.7%) | 0/6 (0%) | 3/20 (15%) | |||
| Pain in extremity | 1/6 (16.7%) | 2/6 (33.3%) | 0/20 (0%) | |||
| Nervous system disorders | ||||||
| Dizziness | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Dysgeusia | 0/6 (0%) | 1/6 (16.7%) | 3/20 (15%) | |||
| Headache | 3/6 (50%) | 1/6 (16.7%) | 2/20 (10%) | |||
| Nervous system disorders - Other, specify | 0/6 (0%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Paresthesia | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Peripheral motor neuropathy | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Peripheral sensory neuropathy | 0/6 (0%) | 0/6 (0%) | 3/20 (15%) | |||
| Syncope | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Tremor | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Psychiatric disorders | ||||||
| Anxiety | 2/6 (33.3%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Depression | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Insomnia | 3/6 (50%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Restlessness | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Renal and urinary disorders | ||||||
| Renal and urinary disorders - Other, specify | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Allergic rhinitis | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Cough | 4/6 (66.7%) | 4/6 (66.7%) | 4/20 (20%) | |||
| Dyspnea | 4/6 (66.7%) | 1/6 (16.7%) | 6/20 (30%) | |||
| Hiccups | 1/6 (16.7%) | 0/6 (0%) | 2/20 (10%) | |||
| Laryngeal inflammation | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Nasal congestion | 2/6 (33.3%) | 0/6 (0%) | 0/20 (0%) | |||
| Pharyngeal necrosis | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Postnasal drip | 1/6 (16.7%) | 0/6 (0%) | 2/20 (10%) | |||
| Productive cough | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Respiratory, thoracic and mediastinal disorders | 0/6 (0%) | 0/6 (0%) | 1/20 (5%) | |||
| Respiratory, thoracic and mediastinal disorders - Other, specify | 1/6 (16.7%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Sore throat | 1/6 (16.7%) | 0/6 (0%) | 1/20 (5%) | |||
| Wheezing | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 2/6 (33.3%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Dry skin | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
| Hyperhidrosis | 2/6 (33.3%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Pruritus | 4/6 (66.7%) | 0/6 (0%) | 1/20 (5%) | |||
| Rash acneiform | 0/6 (0%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Rash maculo-papular | 0/6 (0%) | 0/6 (0%) | 4/20 (20%) | |||
| Skin and subcutaneous tissue disorders - Other, specify | 4/6 (66.7%) | 2/6 (33.3%) | 0/20 (0%) | |||
| Skin/subcutaneous tissue disorders; Other, specify | 1/6 (16.7%) | 4/6 (66.7%) | 3/20 (15%) | |||
| Vascular disorders | ||||||
| Chills | 4/6 (66.7%) | 1/6 (16.7%) | 2/20 (10%) | |||
| Flushing | 1/6 (16.7%) | 0/6 (0%) | 0/20 (0%) | |||
| Hypotension | 0/6 (0%) | 1/6 (16.7%) | 1/20 (5%) | |||
| Vascular disorders - Other, specify | 0/6 (0%) | 1/6 (16.7%) | 0/20 (0%) | |||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Matthew Davids, MD |
|---|---|
| Organization | Dana-Farber Cancer Institute |
| Phone | 617-632-6331 |
| matthew_davids@dfci.harvard.edu |
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