A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors
Study Details
Study Description
Brief Summary
This Phase 1b/2 study will examine the effects of the study drugs, avelumab, binimetinib and talazoparib when given in a 2 (doublet) or 3 (triplet) drug combination, in patients with locally advanced or metastatic RAS-mutant solid tumors. The Phase 1b part of the study will assess if the different study drugs can be given together safely and which doses to use for further research. Phase 2 will test if the study treatments have an effect on tumor size and growth, and gather more information about potential side effects.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 1/Phase 2 |
Detailed Description
This is a Phase 1b/2, open label, multi-center, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of combinations of avelumab, binimetinib and talazoparib in adult patients with metastatic pancreatic ductal adenocarcinoma and other locally advanced or metastatic KRAS- or NRAS-mutant solid tumors.
The Phase 1b part of this study will initially assess doublet drug combinations to determine a recommended dose for further investigation. Following this, the recommended dose for the combination of avelumab, binimetinib and talazoparib (triplet) will be determined. The recommended doses for the doublet and triplet combinations will be used in the Phase 2 part of the study, which will assess the safety and preliminary anti-tumor activity of the study treatments.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Avelumab and binimetinib Open label |
Drug: Avelumab
IV treatment
Other Names:
Drug: Binimetinib
Oral treatment
Other Names:
|
Experimental: Avelumab, binimetinib and talazoparib Open label |
Drug: Avelumab
IV treatment
Other Names:
Drug: Binimetinib
Oral treatment
Other Names:
Drug: Talazoparib
Oral treatment
Other Names:
|
Experimental: Binimetinib and talazoparib. Open label. |
Drug: Binimetinib
Oral treatment
Other Names:
Drug: Talazoparib
Oral treatment
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b [From date of first study treatment to day 28 of study treatment (Up to 28 days)]
Any adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to study drugs and met DLT criteria. DLT was defined as hematologic: Grade 4 neutropenia lasting>5 days; febrile neutropenia; neutropenic infection; Grade >=3 thrombocytopenia with bleed; Grade 4 thrombocytopenia; Grade 4 anemia; non-hematologic: Grade ≥3 toxicities (with some exceptions) ; Grade≥3 creatinine phosphokinase (CPK) with creatinine >= 1.5xbaseline; Grade 3 troponin increase with cardiac toxicity; potential Hy's Law cases; eye disorders: retinopathy or retinal detachment Grade≥3; retinal vascular disorder; Grade≥3 uveitis, blurred vision, flashing lights, floaters or others for >21 consecutive days; other Grade 4; cardiac disorders: absolute LVEF decrease >10% and the LVEF was below LLN; other Grade≥3; respiratory disorders: interstitial lung disease Grade≥2; bronchospasm Grade 3; skin and subcutaneous tissue disorders; non-adherence to treatment schedule; dose reductions.
- Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. [From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).]
Confirmed OR, defined as a complete response (CR) or partial response (PR) per RECIST v1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Both CR and PR must be confirmed by repeated assessments performed no less than 4 weeks after the criteria for response were first met.
Secondary Outcome Measures
- Number of Participants With Adverse Events During the On-Treatment Period [From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) assessed for a maximum duration of up to 31 months]
An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.
- Number of Participants With Hematology Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03 [Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)]
Laboratory abnormalities were graded by NCI CTCAE version 4.03. Anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4.
- Number of Participants With Chemistry Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03 [Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)]
Laboratory abnormalities were graded by NCI CTCAE version 4.03. Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (cpk) increased, creatinine increased, gamma-glutamyl transferase (ggt) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, serum amylase increased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4.
- Predose Concentration During Multiple Dosing (Ctrough) for Avelumab [Pre-dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12.]
Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The lower limit of quantification (LLQ) was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
- Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib [Predose on Day 15 of Cycle 1 (each cycle is 28 days), Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 for avelumab+binimetinib groups, and on Day 8 and Day 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 3 for binimetinib+talazoparib groups]
Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
- Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib [Pre-dose on Days 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and Cycle 3]
Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 25 pg/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
- Maximum Observed Plasma Concentration (Cmax) for Avelumab [Post dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12]
Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
- Maximum Observed Plasma Concentration (Cmax) for Binimetinib [Post dose on Day 1 and Day 8 of Cycle 1]
Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.
- Number of Participants With Anti-drug Antibody (ADA) Categories [from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months]
Samples positive for ADA were analyzed for titer. Blood samples were collected for avelumab immunogenicity testing. Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA was defined as participants with ADA-negative at baseline and had at least one positive post-baseline ADA result; or if participant did not have a baseline sample, the participant had at least one positive post-baseline ADA result.
- Neutralizing Antibodies (nAb) Against Avelumab [from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months]
The category of nAb included nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.
- Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1) [From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).]
OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' (date of first study treatment) until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Clopper-Pearson method was used.
- Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b [From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).]
PFS is defined as the time from the 'start date' (date of first study treatment) to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. CIs were calculated using Brookmeyer and Crowley method.
- Overall Survival (OS) in Phase 1b [From date of first study treatment until the date of death due to any cause (assessed for a maximum duration of up to 31 months).]
OS is defined as the time from the 'start date' (date of first study treatment) to the date of death due to any cause. CIs were calculated using Brookmeyer and Crowley method.
- Time-to-Tumor Response (TTR) in Phase 1b [From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).]
TTR is defined, for patients with an OR, as the time from the 'start date' (date of first study treatment) to the first documentation of objective response (CR or PR) which was subsequently confirmed. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy.
- Duration of Response (DR) in Phase 1b [From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).]
DR is defined, for patients with OR, as the time from the first documentation of objective response (CR or PR) to the date of first documentation of PD or death due to any cause. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy.
- Phase 2: Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression, DNA Damage Repair (DDR) Gene Alterations, and Tumor Mutational Burden (TMB) in Baseline Tumor Tissue. [Baseline]
PD-L1 expression was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. DDR gene alterations was defined as the number of somatic and germline mutations present in a panel of genes associated with DDR in baseline tumor derived nucleic acid, in germline nucleic acid and in circulating tumor DNA. TMB was defined as determination/estimation of the frequency of mutations (total and non-synonymous) present in baseline tumor derived nucleic acid samples and in baseline circulating tumor DNA.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent as follows:
-
Metastatic pancreatic ductal adenocarcinoma; or
-
Phase 2 only: Stage IIIb/IV NSCLC or other advanced solid tumors with documented positive KRAS or NRAS mutation as determined using a validated test performed in a CAP/CLIA-certified laboratory (or other comparable local or regional certification).
-
Have had disease progression during or following at least 1 and not more than 2 prior lines of treatment for advanced or metastatic disease.
-
Patients with NSCLC must have previously received treatment with an anti-PD-1 or anti-PD-L1 agent for advanced disease.
-
Measurable disease as per RECIST v1.1 criteria.
-
Provision of a baseline tumor sample.
-
Age ≥18 years (Japanese patients must be ≥20 years old)
-
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
-
Adequate bone marrow, renal and liver functions.
-
Adequate cardiac function.
-
Informed consent provided.
Exclusion Criteria:
-
Prior treatment with avelumab, a PARP inhibitor or MEK inhibitor.
-
Prior systemic anti-cancer therapy within 2 weeks prior to study enrollment.
-
Persisting toxicity related to prior therapy.
-
Current use of immunosuppressive medication.
-
Known history of immune-mediated colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis, uveitis or iritis.
-
Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
-
Diagnosis of myelodysplastic syndrome (MDS).
-
Known symptomatic brain metastases requiring steroids.
-
Known history of testing positive for HIV or hepatitis.
-
Clinically significant (ie, active) cardiovascular disease.
-
History of thromboembolic or cerebrovascular events.
-
Current or anticipated use of a P-gp inhibitor, inducer, or inhibitor of breast cancer resistance protein (BCRP)
-
Uncontrolled hypertension.
-
Concurrent neuromuscular disorder that is associated with the potential of elevated creatinine kinase.
-
Known history of Gilbert's syndrome.
-
History or current evidence of retinal degenerative disease, retinal vein occlusion (RVO) or current risk factors for RVO.
-
Other acute or chronic medical or psychiatric condition.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Highlands Oncology Group | Fayetteville | Arkansas | United States | 72703 |
2 | Highlands Oncology Group | Rogers | Arkansas | United States | 72758 |
3 | Highlands Oncology Group | Springdale | Arkansas | United States | 72762 |
4 | California Cancer Associates for Research and Excellence, Inc (cCARE) | Encinitas | California | United States | 92024 |
5 | University of Colorado Denver CTO (CTRC) | Aurora | Colorado | United States | 80045 |
6 | University of Colorado Hospital | Aurora | Colorado | United States | 80045 |
7 | Horizon Oncology Research, LLC | Lafayette | Indiana | United States | 47905 |
8 | UPMC Hillman Cancer Center | Pittsburgh | Pennsylvania | United States | 15232 |
9 | The University of Texas MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
10 | University of Utah, Huntsman Cancer Hospital | Salt Lake City | Utah | United States | 84112 |
11 | University of Utah, Huntsman Cancer Institute | Salt Lake City | Utah | United States | 84112 |
12 | Institut Jules Bordet | Brussels | Belgium | 1000 | |
13 | UZ Gent | Gent | Belgium | 9000 | |
14 | Singapore National Eye Centre | Singapore | Singapore | 168751 | |
15 | Singapore General Hospital | Singapore | Singapore | 169608 | |
16 | SingHealth Investigational Medicine Unit | Singapore | Singapore | 169608 | |
17 | National Heart Centre Singapore | Singapore | Singapore | 169609 | |
18 | National Cancer Centre Singapore | Singapore | Singapore | 169610 |
Sponsors and Collaborators
- Pfizer
Investigators
- Study Director: Pfizer CT.gov Call Center, Pfizer
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- B9991033
- 2018-000124-34
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | Forty six participants were screened and 36 were enrolled, one was not treated. This study was planned to included 2 periods: phase 1b and phase 2. Due to the early termination of this study, only the doublet combinations (avelumab + binimetinib and binimetinib + talazoparib) in Phase 1b to find a safe dose were conducted, and neither the triplet combination of Phase 1b nor Phase 2 was initiated. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg every 2 weeks (Q2W) in combination with binimetinib at 30 mg twice daily (BID) orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Period Title: Overall Study | ||||
STARTED | 10 | 12 | 7 | 6 |
Received Treatment | 10 | 12 | 7 | 6 |
COMPLETED | 0 | 0 | 0 | 0 |
NOT COMPLETED | 10 | 12 | 7 | 6 |
Baseline Characteristics
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) | Total |
---|---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Total of all reporting groups |
Overall Participants | 10 | 12 | 7 | 6 | 35 |
Age (Years) [Mean (Standard Deviation) ] | |||||
Mean (Standard Deviation) [Years] |
65.30
(11.10)
|
65.25
(8.56)
|
68.57
(9.61)
|
68.00
(9.94)
|
66.40
(9.45)
|
Sex: Female, Male (Count of Participants) | |||||
Female |
4
40%
|
3
25%
|
6
85.7%
|
3
50%
|
16
45.7%
|
Male |
6
60%
|
9
75%
|
1
14.3%
|
3
50%
|
19
54.3%
|
Ethnicity (NIH/OMB) (Count of Participants) | |||||
Hispanic or Latino |
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
1
2.9%
|
Not Hispanic or Latino |
10
100%
|
12
100%
|
5
71.4%
|
5
83.3%
|
32
91.4%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
1
14.3%
|
1
16.7%
|
2
5.7%
|
Race/Ethnicity, Customized (Count of Participants) | |||||
Asian |
1
10%
|
0
0%
|
0
0%
|
0
0%
|
1
2.9%
|
White |
9
90%
|
12
100%
|
6
85.7%
|
5
83.3%
|
32
91.4%
|
Not Reported |
0
0%
|
0
0%
|
1
14.3%
|
1
16.7%
|
2
5.7%
|
Outcome Measures
Title | Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b |
---|---|
Description | Any adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to study drugs and met DLT criteria. DLT was defined as hematologic: Grade 4 neutropenia lasting>5 days; febrile neutropenia; neutropenic infection; Grade >=3 thrombocytopenia with bleed; Grade 4 thrombocytopenia; Grade 4 anemia; non-hematologic: Grade ≥3 toxicities (with some exceptions) ; Grade≥3 creatinine phosphokinase (CPK) with creatinine >= 1.5xbaseline; Grade 3 troponin increase with cardiac toxicity; potential Hy's Law cases; eye disorders: retinopathy or retinal detachment Grade≥3; retinal vascular disorder; Grade≥3 uveitis, blurred vision, flashing lights, floaters or others for >21 consecutive days; other Grade 4; cardiac disorders: absolute LVEF decrease >10% and the LVEF was below LLN; other Grade≥3; respiratory disorders: interstitial lung disease Grade≥2; bronchospasm Grade 3; skin and subcutaneous tissue disorders; non-adherence to treatment schedule; dose reductions. |
Time Frame | From date of first study treatment to day 28 of study treatment (Up to 28 days) |
Outcome Measure Data
Analysis Population Description |
---|
The safety analysis set included all enrolled participants who receive at least 1 dose of study treatment. The DLT-evaluable analysis set was a subset of the safety analysis set and included all enrolled participants in Phase 1b who were eligible for the study, received at least one dose of the combination treatment, and either experienced DLT during the first cycle (28 days) of treatment, or completed the DLT observation period for the first cycle of treatment without DLT. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 11 | 6 | 5 |
Count of Participants [Participants] |
3
30%
|
5
41.7%
|
2
28.6%
|
2
33.3%
|
Title | Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. |
---|---|
Description | Confirmed OR, defined as a complete response (CR) or partial response (PR) per RECIST v1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Both CR and PR must be confirmed by repeated assessments performed no less than 4 weeks after the criteria for response were first met. |
Time Frame | From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months). |
Outcome Measure Data
Analysis Population Description |
---|
Due to the early termination of this study, Phase 2 was not initiated and therefore no Phase 2 efficacy results were collected and summarized. |
Arm/Group Title | Avelumab Binimetinib and Talazoparib |
---|---|
Arm/Group Description | Since phase 2 was not initiated, the dose and details of arm haven't been confirmed. |
Measure Participants | 0 |
Title | Number of Participants With Adverse Events During the On-Treatment Period |
---|---|
Description | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. |
Time Frame | From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) assessed for a maximum duration of up to 31 months |
Outcome Measure Data
Analysis Population Description |
---|
The safety analysis set included all enrolled participants who received at least 1 dose of study treatment. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
participants with TEAEs |
10
100%
|
12
100%
|
7
100%
|
6
100%
|
participants with grade ≥ 3 TEAEs |
10
100%
|
9
75%
|
4
57.1%
|
5
83.3%
|
participants with treatment-related TEAEs |
10
100%
|
12
100%
|
7
100%
|
6
100%
|
participants with grade ≥ 3 treatment-related TEAEs |
8
80%
|
4
33.3%
|
0
0%
|
3
50%
|
participants with serious TEAEs |
6
60%
|
9
75%
|
3
42.9%
|
3
50%
|
participants with serious treatment-related TEAEs |
2
20%
|
1
8.3%
|
0
0%
|
2
33.3%
|
participants with TEAEs leading to discontinuation of Avelumab |
1
10%
|
2
16.7%
|
0
0%
|
0
0%
|
participants with TEAEs leading to discontinuation of Binimetinib |
3
30%
|
4
33.3%
|
1
14.3%
|
2
33.3%
|
participants with TEAEs leading to discontinuation of Talazoparib |
0
0%
|
0
0%
|
1
14.3%
|
2
33.3%
|
participants with TEAEs leading to discontinuation of any study drug |
3
30%
|
4
33.3%
|
1
14.3%
|
2
33.3%
|
participants with TEAEs leading to discontinuation of all study drugs |
1
10%
|
1
8.3%
|
1
14.3%
|
0
0%
|
participants with treatment-related TEAEs leading to discontinuation of Avelumab |
1
10%
|
1
8.3%
|
0
0%
|
0
0%
|
participants with treatment-related TEAEs leading to discontinuation of Binimetinib |
3
30%
|
3
25%
|
0
0%
|
1
16.7%
|
participants with treatment-related TEAEs leading to discontinuation of Talazoparib |
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
participants with treatment-related TEAEs leading to discontinuation of any study drug |
3
30%
|
3
25%
|
0
0%
|
1
16.7%
|
participants with treatment-related TEAEs leading to discontinuation of all study drugs |
1
10%
|
0
0%
|
0
0%
|
0
0%
|
participants with TEAEs leading to death |
0
0%
|
3
25%
|
2
28.6%
|
1
16.7%
|
participants with treatment-related TEAEs leading to death |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
participants with infusion-related reactions (IRRs) |
3
30%
|
1
8.3%
|
0
0%
|
0
0%
|
Title | Number of Participants With Hematology Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03 |
---|---|
Description | Laboratory abnormalities were graded by NCI CTCAE version 4.03. Anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4. |
Time Frame | Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months) |
Outcome Measure Data
Analysis Population Description |
---|
The safety analysis set included all enrolled participants who received at least 1 dose of study treatment. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
ANEMIA |
9
90%
|
9
75%
|
7
100%
|
5
83.3%
|
HEMOGLOBIN INCREASED |
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
LYMPHOCYTE COUNT DECREASED |
6
60%
|
7
58.3%
|
5
71.4%
|
6
100%
|
LYMPHOCYTE COUNT INCREASED |
1
10%
|
1
8.3%
|
0
0%
|
0
0%
|
NEUTROPHIL COUNT DECREASED |
0
0%
|
1
8.3%
|
1
14.3%
|
2
33.3%
|
PLATELET COUNT DECREASED |
3
30%
|
3
25%
|
4
57.1%
|
3
50%
|
WHITE BLOOD CELL DECREASED |
2
20%
|
2
16.7%
|
0
0%
|
4
66.7%
|
Title | Number of Participants With Chemistry Laboratory Abnormalities During the On-Treatment Period Graded by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE), Version 4.03 |
---|---|
Description | Laboratory abnormalities were graded by NCI CTCAE version 4.03. Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (cpk) increased, creatinine increased, gamma-glutamyl transferase (ggt) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, serum amylase increased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4. |
Time Frame | Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months) |
Outcome Measure Data
Analysis Population Description |
---|
The safety analysis set included all enrolled participants who received at least 1 dose of study treatment. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
ALANINE AMINOTRANSFERASE INCREASED |
5
50%
|
5
41.7%
|
3
42.9%
|
2
33.3%
|
ALKALINE PHOSPHATASE INCREASED |
9
90%
|
7
58.3%
|
6
85.7%
|
5
83.3%
|
ASPARTATE AMINOTRANSFERASE INCREASED |
8
80%
|
8
66.7%
|
6
85.7%
|
3
50%
|
BLOOD BILIRUBIN INCREASED |
4
40%
|
0
0%
|
0
0%
|
1
16.7%
|
CPK INCREASED |
6
60%
|
7
58.3%
|
3
42.9%
|
1
16.7%
|
CREATININE INCREASED |
8
80%
|
11
91.7%
|
6
85.7%
|
4
66.7%
|
GGT INCREASED |
8
80%
|
4
33.3%
|
6
85.7%
|
2
33.3%
|
HYPERCALCEMIA |
2
20%
|
1
8.3%
|
1
14.3%
|
0
0%
|
HYPERGLYCEMIA |
5
50%
|
6
50%
|
4
57.1%
|
5
83.3%
|
HYPERKALEMIA |
1
10%
|
3
25%
|
1
14.3%
|
0
0%
|
HYPERMAGNESEMIA |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
HYPERNATREMIA |
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
HYPOALBUMINEMIA |
7
70%
|
11
91.7%
|
5
71.4%
|
3
50%
|
HYPOCALCEMIA |
0
0%
|
1
8.3%
|
0
0%
|
0
0%
|
HYPOGLYCEMIA |
2
20%
|
2
16.7%
|
0
0%
|
1
16.7%
|
HYPOKALEMIA |
4
40%
|
1
8.3%
|
3
42.9%
|
3
50%
|
HYPOMAGNESEMIA |
3
30%
|
2
16.7%
|
2
28.6%
|
1
16.7%
|
HYPONATREMIA |
5
50%
|
4
33.3%
|
2
28.6%
|
0
0%
|
HYPOPHOSPHATEMIA |
3
30%
|
1
8.3%
|
1
14.3%
|
0
0%
|
LIPASE INCREASED |
1
10%
|
3
25%
|
0
0%
|
1
16.7%
|
SERUM AMYLASE INCREASED |
2
20%
|
5
41.7%
|
0
0%
|
0
0%
|
Title | Predose Concentration During Multiple Dosing (Ctrough) for Avelumab |
---|---|
Description | Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The lower limit of quantification (LLQ) was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. |
Time Frame | Pre-dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12. |
Outcome Measure Data
Analysis Population Description |
---|
Number of participants analyzed: participants who had at least 1 concentration measurement for avelumab. Therefore, only 2 treatment groups including avelumab were analyzed. Number analyzed: participants who had avelumab concentrations above the LLQ at specific time point. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) |
---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. |
Measure Participants | 10 | 12 |
CYCLE1_DAY15 |
22.38
(59)
|
28.82
(57)
|
CYCLE2_DAY1 |
29.26
(39)
|
38.28
(52)
|
CYCLE2_DAY15 |
40.86
(42)
|
37.26
(59)
|
CYCLE3_DAY1 |
31.30
(NA)
|
34.69
(75)
|
CYCLE5_DAY1 |
28.00
(NA)
|
36.51
(38)
|
CYCLE9_DAY1 |
46.49
(NA)
|
|
CYCLE12_DAY1 |
38.77
(NA)
|
Title | Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib |
---|---|
Description | Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. |
Time Frame | Predose on Day 15 of Cycle 1 (each cycle is 28 days), Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 for avelumab+binimetinib groups, and on Day 8 and Day 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 3 for binimetinib+talazoparib groups |
Outcome Measure Data
Analysis Population Description |
---|
Number of participants analyzed: participants who had at least 1 concentration measurement for binimetinib. Number analyzed: participants who had binimetinib concentration values above the LLQ at specific time point. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
CYCLE1_DAY8 |
82.90
(NA)
|
128.6
(49)
|
||
CYCLE1_DAY15 |
87.85
(48)
|
88.67
(16)
|
22.80
(NA)
|
|
CYCLE2_DAY1 |
55.71
(56)
|
107.5
(NA)
|
||
CYCLE2_DAY15 |
93.45
(90)
|
88.33
(NA)
|
||
CYCLE3_DAY1 |
56.60
(NA)
|
74.90
(NA)
|
Title | Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib |
---|---|
Description | Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 25 pg/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. |
Time Frame | Pre-dose on Days 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and Cycle 3 |
Outcome Measure Data
Analysis Population Description |
---|
Number of participants analyzed: participants who had at least 1 concentration measurement for talazoparib. Therefore, only 2 treatment groups including talazoparib were analyzed. Number analyzed: participants who had talazoparib concentrations above the LLQ at specific time point. |
Arm/Group Title | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|
Arm/Group Description | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 7 | 6 |
CYCLE1_DAY8 |
4856
(NA)
|
2926
(49)
|
CYCLE1_DAY15 |
5960
(NA)
|
2683
(65)
|
CYCLE2_DAY1 |
8620
(NA)
|
2753
(NA)
|
CYCLE3_DAY1 |
1520
(NA)
|
Title | Maximum Observed Plasma Concentration (Cmax) for Avelumab |
---|---|
Description | Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. |
Time Frame | Post dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12 |
Outcome Measure Data
Analysis Population Description |
---|
Number of participants analyzed: participants who had at least 1 concentration measurement for avelumab. Therefore, only 2 treatment groups including avelumab were analyzed. Number analyzed: participants who had avelumab concentrations above the LLQ at specific time point. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) |
---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. |
Measure Participants | 10 | 12 |
CYCLE1_DAY1 |
205.3
(22)
|
248.6
(14)
|
CYCLE1_DAY15 |
214.2
(20)
|
237.4
(45)
|
CYCLE2_DAY1 |
213.0
(20)
|
241.5
(26)
|
CYCLE2_DAY15 |
211.5
(17)
|
243.0
(19)
|
CYCLE3_DAY1 |
176.0
(NA)
|
233.7
(28)
|
CYCLE5_DAY1 |
188.0
(NA)
|
241.9
(21)
|
CYCLE9_DAY1 |
257.0
(NA)
|
|
CYCLE12_DAY1 |
255.8
(NA)
|
Title | Maximum Observed Plasma Concentration (Cmax) for Binimetinib |
---|---|
Description | Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage. |
Time Frame | Post dose on Day 1 and Day 8 of Cycle 1 |
Outcome Measure Data
Analysis Population Description |
---|
Number of participants analyzed: participants who had at least 1 concentration measurement for binimetinib. Number analyzed: participants who had binimetinib concentrations above the LLQ at specific time point. When Cmax for binimetinib was planned to be evaluated, data collecting for Avelumab+Binimetinib cohort had already been done. Therefore, data of Cmax for binimetinib in Avelumab+Binimetinib groups hadn't been collected. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 0 | 0 | 7 | 6 |
CYCLE1_DAY1 |
370.24
(64)
|
331.74
(63)
|
||
CYCLE1_DAY8 |
183.53
(180)
|
446.81
(59)
|
Title | Number of Participants With Anti-drug Antibody (ADA) Categories |
---|---|
Description | Samples positive for ADA were analyzed for titer. Blood samples were collected for avelumab immunogenicity testing. Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA was defined as participants with ADA-negative at baseline and had at least one positive post-baseline ADA result; or if participant did not have a baseline sample, the participant had at least one positive post-baseline ADA result. |
Time Frame | from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months |
Outcome Measure Data
Analysis Population Description |
---|
Participants in the safety analysis set had at least one ADA/nAb sample collected for avelumab, so only two groups (Avelumab+Binimetinib 30mg [Phase 1b] and Avelumab+Binimetinib 45mg [Phase 1b]) were analyzed. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) |
---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. |
Measure Participants | 10 | 12 |
ADA never-positive |
8
80%
|
11
91.7%
|
ADA ever-positive |
2
20%
|
1
8.3%
|
Title | Neutralizing Antibodies (nAb) Against Avelumab |
---|---|
Description | The category of nAb included nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response. |
Time Frame | from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months |
Outcome Measure Data
Analysis Population Description |
---|
Participants in the safety analysis set had at least one ADA/nAb sample collected for avelumab. Due to the low observed immunogenicity rate, nAb analysis was not conducted. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) |
---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. |
Measure Participants | 0 | 0 |
Title | Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1) |
---|---|
Description | OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' (date of first study treatment) until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Clopper-Pearson method was used. |
Time Frame | From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months). |
Outcome Measure Data
Analysis Population Description |
---|
The full analysis set included all enrolled participants who received at least 1 dose of study treatment. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
Number (95% Confidence Interval) [Percentage of participants] |
0
0%
|
8.3
69.2%
|
0
0%
|
0
0%
|
Title | Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b |
---|---|
Description | PFS is defined as the time from the 'start date' (date of first study treatment) to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. CIs were calculated using Brookmeyer and Crowley method. |
Time Frame | From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months). |
Outcome Measure Data
Analysis Population Description |
---|
The full analysis set included all enrolled participants who received at least 1 dose of study treatment. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
Median (95% Confidence Interval) [months] |
1.7
|
3.3
|
1.6
|
1.8
|
Title | Overall Survival (OS) in Phase 1b |
---|---|
Description | OS is defined as the time from the 'start date' (date of first study treatment) to the date of death due to any cause. CIs were calculated using Brookmeyer and Crowley method. |
Time Frame | From date of first study treatment until the date of death due to any cause (assessed for a maximum duration of up to 31 months). |
Outcome Measure Data
Analysis Population Description |
---|
The full analysis set included all enrolled participants who received at least 1 dose of study treatment. |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 10 | 12 | 7 | 6 |
Median (95% Confidence Interval) [months] |
5.9
|
8.0
|
2.9
|
10.7
|
Title | Time-to-Tumor Response (TTR) in Phase 1b |
---|---|
Description | TTR is defined, for patients with an OR, as the time from the 'start date' (date of first study treatment) to the first documentation of objective response (CR or PR) which was subsequently confirmed. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. |
Time Frame | From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months). |
Outcome Measure Data
Analysis Population Description |
---|
The full analysis set included all enrolled participants who received at least 1 dose of study treatment and achieved objective response: only 1 participant in the Avelumab+Binimetinib 45mg (Phase 1b) group achieved OR. The summary of this endpoint cannot be estimated due to small sample size (1 participant). |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 0 | 0 | 0 | 0 |
Title | Duration of Response (DR) in Phase 1b |
---|---|
Description | DR is defined, for patients with OR, as the time from the first documentation of objective response (CR or PR) to the date of first documentation of PD or death due to any cause. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. |
Time Frame | From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months). |
Outcome Measure Data
Analysis Population Description |
---|
The full analysis set included all enrolled participants who received at least 1 dose of study treatment and achieved objective response: only 1 participant in the Avelumab+Binimetinib 45mg (Phase 1b) group achieved OR. The summary of this endpoint cannot be estimated due to small sample size (1 participant). |
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) |
---|---|---|---|---|
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. |
Measure Participants | 0 | 0 | 0 | 0 |
Title | Phase 2: Number of Participants With Programmed Death-Ligand 1 (PD-L1) Expression, DNA Damage Repair (DDR) Gene Alterations, and Tumor Mutational Burden (TMB) in Baseline Tumor Tissue. |
---|---|
Description | PD-L1 expression was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. DDR gene alterations was defined as the number of somatic and germline mutations present in a panel of genes associated with DDR in baseline tumor derived nucleic acid, in germline nucleic acid and in circulating tumor DNA. TMB was defined as determination/estimation of the frequency of mutations (total and non-synonymous) present in baseline tumor derived nucleic acid samples and in baseline circulating tumor DNA. |
Time Frame | Baseline |
Outcome Measure Data
Analysis Population Description |
---|
The biomarkers were for the phase 2 part. since phase 2 was not initiated, the results was not provided. |
Arm/Group Title | Avelumab Binimetinib and Talazoparib |
---|---|
Arm/Group Description | Since phase 2 was not initiated, the dose and details of arm haven't been confirmed. |
Measure Participants | 0 |
Adverse Events
Time Frame | From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) assessed for a maximum duration of up to 31 months | |||||||
---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||||
Arm/Group Title | Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) | ||||
Arm/Group Description | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 30 mg BID orally on a continuous daily dosing schedule. | Avelumab was administered at a fixed dose of 800 mg Q2W in combination with binimetinib at 45 mg BID orally on a continuous daily dosing schedule. | Binimetinib 30 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | Binimetinib 45 mg was administered orally BID (7 days on / 7 days off) with talazoparib at 0.75 mg once daily (QD) orally on a continuous dosing schedule. | ||||
All Cause Mortality |
||||||||
Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 9/10 (90%) | 9/12 (75%) | 5/7 (71.4%) | 3/6 (50%) | ||||
Serious Adverse Events |
||||||||
Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 6/10 (60%) | 9/12 (75%) | 3/7 (42.9%) | 3/6 (50%) | ||||
Blood and lymphatic system disorders | ||||||||
Anaemia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Cardiac disorders | ||||||||
Myocardial infarction | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Gastrointestinal disorders | ||||||||
Ascites | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Diarrhoea | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Gastric haemorrhage | 0/10 (0%) | 1/12 (8.3%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Gastric ulcer | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Nausea | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Small intestinal obstruction | 0/10 (0%) | 1/12 (8.3%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Vomiting | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 1/6 (16.7%) | ||||
General disorders | ||||||||
Chills | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Disease progression | 0/10 (0%) | 3/12 (25%) | 1/7 (14.3%) | 1/6 (16.7%) | ||||
Fatigue | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Mucosal inflammation | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Pyrexia | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Systemic inflammatory response syndrome | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Hepatobiliary disorders | ||||||||
Hyperbilirubinaemia | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Infections and infestations | ||||||||
Pneumonia | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Sepsis | 2/10 (20%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Injury, poisoning and procedural complications | ||||||||
Fall | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Skin laceration | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Investigations | ||||||||
Alanine aminotransferase increased | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Aspartate aminotransferase increased | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Metabolism and nutrition disorders | ||||||||
Dehydration | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Hyponatraemia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||
Tumour associated fever | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Nervous system disorders | ||||||||
Encephalopathy | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Respiratory, thoracic and mediastinal disorders | ||||||||
Dyspnoea | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Pneumonitis | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Pulmonary embolism | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Respiratory failure | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Vascular disorders | ||||||||
Deep vein thrombosis | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Embolism | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Other (Not Including Serious) Adverse Events |
||||||||
Avelumab+Binimetinib 30mg (Phase 1b) | Avelumab+Binimetinib 45mg (Phase 1b) | Binimetinib 30mg+Talazoparib 0.75mg (Phase 1b) | Binimetinib 45mg+Talazoparib 0.75mg (Phase 1b) | |||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 10/10 (100%) | 12/12 (100%) | 7/7 (100%) | 6/6 (100%) | ||||
Blood and lymphatic system disorders | ||||||||
Anaemia | 0/10 (0%) | 3/12 (25%) | 2/7 (28.6%) | 2/6 (33.3%) | ||||
Iron deficiency anaemia | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Leukocytosis | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Endocrine disorders | ||||||||
Hypothyroidism | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Eye disorders | ||||||||
Cataract | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Detachment of retinal pigment epithelium | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Dry eye | 0/10 (0%) | 1/12 (8.3%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Glaucoma | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Macular oedema | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Ocular hyperaemia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Periorbital oedema | 2/10 (20%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Photopsia | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Retinopathy | 0/10 (0%) | 3/12 (25%) | 0/7 (0%) | 0/6 (0%) | ||||
Subretinal fluid | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Vision blurred | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 2/6 (33.3%) | ||||
Gastrointestinal disorders | ||||||||
Abdominal discomfort | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Abdominal pain | 3/10 (30%) | 2/12 (16.7%) | 1/7 (14.3%) | 1/6 (16.7%) | ||||
Abdominal pain upper | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Ascites | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Cheilitis | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Constipation | 2/10 (20%) | 1/12 (8.3%) | 1/7 (14.3%) | 2/6 (33.3%) | ||||
Diarrhoea | 2/10 (20%) | 4/12 (33.3%) | 2/7 (28.6%) | 3/6 (50%) | ||||
Dry mouth | 0/10 (0%) | 2/12 (16.7%) | 0/7 (0%) | 0/6 (0%) | ||||
Gastrooesophageal reflux disease | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Lip blister | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Nausea | 2/10 (20%) | 4/12 (33.3%) | 3/7 (42.9%) | 4/6 (66.7%) | ||||
Obstruction gastric | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Retching | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Toothache | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Vomiting | 3/10 (30%) | 4/12 (33.3%) | 4/7 (57.1%) | 2/6 (33.3%) | ||||
General disorders | ||||||||
Fatigue | 2/10 (20%) | 4/12 (33.3%) | 4/7 (57.1%) | 1/6 (16.7%) | ||||
Mucosal inflammation | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Non-cardiac chest pain | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Oedema peripheral | 1/10 (10%) | 4/12 (33.3%) | 1/7 (14.3%) | 1/6 (16.7%) | ||||
Pain | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Peripheral swelling | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Pyrexia | 3/10 (30%) | 1/12 (8.3%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Hepatobiliary disorders | ||||||||
Hepatic pain | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Immune system disorders | ||||||||
Hypersensitivity | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Infections and infestations | ||||||||
Candida infection | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Clostridium difficile infection | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Nail infection | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Oral candidiasis | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Oral herpes | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Rash pustular | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Sinusitis | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Skin infection | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Urinary tract infection | 0/10 (0%) | 2/12 (16.7%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Wound infection | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Injury, poisoning and procedural complications | ||||||||
Animal bite | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Eye contusion | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Fall | 0/10 (0%) | 1/12 (8.3%) | 1/7 (14.3%) | 1/6 (16.7%) | ||||
Infusion related reaction | 3/10 (30%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Skin wound | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Investigations | ||||||||
Activated partial thromboplastin time prolonged | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Alanine aminotransferase increased | 4/10 (40%) | 2/12 (16.7%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Ammonia increased | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Aspartate aminotransferase increased | 5/10 (50%) | 3/12 (25%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Blood alkaline phosphatase increased | 2/10 (20%) | 1/12 (8.3%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Blood creatine phosphokinase increased | 3/10 (30%) | 4/12 (33.3%) | 3/7 (42.9%) | 0/6 (0%) | ||||
Blood creatinine increased | 0/10 (0%) | 3/12 (25%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Ejection fraction decreased | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Fibrin D dimer increased | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Gamma-glutamyltransferase increased | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
International normalised ratio increased | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Lipase increased | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Lymphocyte count decreased | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Neutrophil count decreased | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Platelet count decreased | 0/10 (0%) | 0/12 (0%) | 2/7 (28.6%) | 2/6 (33.3%) | ||||
Troponin T increased | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Weight decreased | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Metabolism and nutrition disorders | ||||||||
Decreased appetite | 0/10 (0%) | 1/12 (8.3%) | 1/7 (14.3%) | 2/6 (33.3%) | ||||
Dehydration | 2/10 (20%) | 2/12 (16.7%) | 2/7 (28.6%) | 1/6 (16.7%) | ||||
Hyperkalaemia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Hyperphosphataemia | 0/10 (0%) | 3/12 (25%) | 0/7 (0%) | 0/6 (0%) | ||||
Hypoalbuminaemia | 1/10 (10%) | 2/12 (16.7%) | 0/7 (0%) | 0/6 (0%) | ||||
Hypocalcaemia | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Hypokalaemia | 2/10 (20%) | 0/12 (0%) | 2/7 (28.6%) | 2/6 (33.3%) | ||||
Hyponatraemia | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Hypophosphataemia | 0/10 (0%) | 3/12 (25%) | 0/7 (0%) | 0/6 (0%) | ||||
Vitamin B12 deficiency | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Vitamin D deficiency | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Musculoskeletal and connective tissue disorders | ||||||||
Arthralgia | 1/10 (10%) | 1/12 (8.3%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Back pain | 0/10 (0%) | 2/12 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Coccydynia | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Flank pain | 0/10 (0%) | 2/12 (16.7%) | 0/7 (0%) | 0/6 (0%) | ||||
Muscle spasms | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Myalgia | 1/10 (10%) | 0/12 (0%) | 2/7 (28.6%) | 0/6 (0%) | ||||
Pain in extremity | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Nervous system disorders | ||||||||
Burning sensation | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Dizziness | 0/10 (0%) | 1/12 (8.3%) | 2/7 (28.6%) | 1/6 (16.7%) | ||||
Dysgeusia | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Hypoaesthesia | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Neuropathy peripheral | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Sciatica | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Tension headache | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Tremor | 1/10 (10%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Psychiatric disorders | ||||||||
Anxiety | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Insomnia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Reproductive system and breast disorders | ||||||||
Benign prostatic hyperplasia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Respiratory, thoracic and mediastinal disorders | ||||||||
Cough | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Dyspnoea | 0/10 (0%) | 2/12 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Hypoxia | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Oropharyngeal pain | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Pneumonitis | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Productive cough | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Pulmonary embolism | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Respiratory tract congestion | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Upper-airway cough syndrome | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Skin and subcutaneous tissue disorders | ||||||||
Dermatitis acneiform | 4/10 (40%) | 3/12 (25%) | 2/7 (28.6%) | 3/6 (50%) | ||||
Dry skin | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Erythema | 0/10 (0%) | 1/12 (8.3%) | 0/7 (0%) | 0/6 (0%) | ||||
Erythema multiforme | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Pruritus | 2/10 (20%) | 2/12 (16.7%) | 0/7 (0%) | 0/6 (0%) | ||||
Rash | 5/10 (50%) | 7/12 (58.3%) | 2/7 (28.6%) | 1/6 (16.7%) | ||||
Rash maculo-papular | 2/10 (20%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Vascular disorders | ||||||||
Deep vein thrombosis | 0/10 (0%) | 0/12 (0%) | 1/7 (14.3%) | 0/6 (0%) | ||||
Diastolic hypertension | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Embolism | 1/10 (10%) | 0/12 (0%) | 0/7 (0%) | 0/6 (0%) | ||||
Haematoma | 0/10 (0%) | 0/12 (0%) | 0/7 (0%) | 1/6 (16.7%) | ||||
Hypertension | 1/10 (10%) | 4/12 (33.3%) | 0/7 (0%) | 1/6 (16.7%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Results Point of Contact
Name/Title | Pfizer ClinicalTrials.gov Call Center |
---|---|
Organization | Pfizer, Inc. |
Phone | 1-800-718-1021 |
ClinicalTrials.gov_Inquiries@pfizer.com |
- B9991033
- 2018-000124-34