Pancreatic CancerPhase 1/2NCT03637491
A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors
A Phase 1/2 study testing Avelumab, Binimetinib and Talazoparib in people with Pancreatic Cancer, run by Pfizer at 18 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pancreatic Cancer
- What is being tested?
- Avelumab, Binimetinib and Talazoparib
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 18 sitesin 3 countries
- Study dates
- 15 Aug 2018to 2 Feb 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
18 sites in 3 countries.
18 sites in 3 countries
United States11 sites
University of Colorado Denver CTO (CTRC)
Aurora, Colorado, 80045
University of Colorado Hospital
Aurora, Colorado, 80045
California Cancer Associates for Research and Excellence, Inc (cCARE)
Encinitas, California, 92024
Highlands Oncology Group
Fayetteville, Arkansas, 72703
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
Horizon Oncology Research, LLC
Lafayette, Indiana, 47905
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
Highlands Oncology Group
Rogers, Arkansas, 72758
University of Utah, Huntsman Cancer Hospital
Salt Lake City, Utah, 84112
University of Utah, Huntsman Cancer Institute
Salt Lake City, Utah, 84112
Highlands Oncology Group
Springdale, Arkansas, 72762
Singapore5 sites
Singapore National Eye Centre
Singapore, 168751
Singapore General Hospital
Singapore, 169608
SingHealth Investigational Medicine Unit
Singapore, 169608
National Heart Centre Singapore
Singapore, 169609
National Cancer Centre Singapore
Singapore, 169610
About this study
Official title: A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT SOLID TUMORS
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.
Read the 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.
- Conditions
- Pancreatic Cancer
- Being tested
- Avelumab, Binimetinib, Talazoparib
- Keywords
- KRAS, NRAS, PDAC, Pancreatic Cancer
- Medical subject headings
- Pancreatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AvelumabDrug
Also called MSB0010718C
IV treatment
BinimetinibDrug
Also called MEK162, ARRY-438162
Oral treatment
TalazoparibDrug
Also called MDV3800, BMN 673
Oral treatment
| Study group | Role | What they receive |
|---|---|---|
| Avelumab and binimetinib | Experimental | Open label Receives: Drug: Avelumab; Drug: Binimetinib |
| Avelumab, binimetinib and talazoparib | Experimental | Open label Receives: Drug: Avelumab; Drug: Binimetinib; Drug: Talazoparib |
| Binimetinib and talazoparib. | Experimental | Open label. Receives: Drug: Binimetinib; Drug: Talazoparib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b
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.
Measured: From date of first study treatment to day 28 of study treatment (Up to 28 days)
Phase 2: Confirmed Objective Response (OR) Based on Investigator Assessment Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
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.
Measured: 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).
Secondary outcomes (16)
Number of Participants With Adverse Events During the On-Treatment Period
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.
Measured: 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
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
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.
Measured: 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)
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
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.
Measured: 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)
Predose Concentration During Multiple Dosing (Ctrough) for Avelumab
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.
Measured: 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.
Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib
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.
Measured: 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
Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib
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.
Measured: 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
Maximum Observed Plasma Concentration (Cmax) for Avelumab
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.
Measured: 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
Maximum Observed Plasma Concentration (Cmax) for Binimetinib
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.
Measured: Post dose on Day 1 and Day 8 of Cycle 1
Number of Participants With Anti-drug Antibody (ADA) Categories
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.
Measured: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
Neutralizing Antibodies (nAb) Against Avelumab
The category of nAb included nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.
Measured: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1)
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.
Measured: 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).
Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b
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.
Measured: 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).
Overall Survival (OS) in Phase 1b
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.
Measured: 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).
Time-to-Tumor Response (TTR) in Phase 1b
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.
Measured: 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).
Duration of Response (DR) in Phase 1b
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.
Measured: 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).
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.
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.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Aug 2018
- Study start15 Aug 2018
- Primary completion3 Dec 2020
- Study completion2 Feb 2021
Why it stopped: Available clinical data has shown limited anti-tumor activity and reaching target study drug dose levels may not be feasible.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Pancreatic CancerStudies of the same condition, open and under way.
- More trials run by PfizerThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- Pfizer
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Pfizer CT.gov Call Center, Study director, Pfizer
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03637491
- Sponsor's protocol ID
- B9991033
- Other IDs
- 2018-000124-34, 2018
- Status last verified
- Dec 2021
- First submitted
- 10 Aug 2018
- Last updated
- 26 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.
Publications
Rodon Ahnert J, Tan DS, Garrido-Laguna I, Harb W, Bessudo A, Beck JT, Rottey S, Bahary N, Kotecki N, Zhu Z, Deng S, Kowalski K, Wei C, Pathan N, Laliberte RJ, Messersmith WA. Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. ESMO Open. 2023 Aug;8(4):101584. doi: 10.1016/j.esmoop.2023.101584. Epub 2023 Jun 26.
PubMed 37379764Sun C, Fang Y, Labrie M, Li X, Mills GB. Systems approach to rational combination therapy: PARP inhibitors. Biochem Soc Trans. 2020 Jun 30;48(3):1101-1108. doi: 10.1042/BST20191092.
PubMed 32379297
Study at a glance
From the registry record, last updated by the sponsor on 26 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF COMBINATIONS OF AVELUMAB, BINIMETINIB AND TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC RAS-MUTANT SOLID TUMORS
- ClinicalTrials.gov ID
- NCT03637491
- Acronym / sponsor ID
- B9991033
- Conditions
- Pancreatic Cancer
- Keywords
- KRAS, NRAS, PDAC, Pancreatic Cancer
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Available clinical data has shown limited anti-tumor activity and reaching target study drug dose levels may not be feasible.
- Enrolment
- 36 participants (actual)
- Lead sponsor
- PfizerIndustry (pharma, biotech, devices)
- Study start
- 15 Aug 2018 (actual)
- Primary completion
- 3 Dec 2020 (actual)
- Study completion
- 2 Feb 2021 (actual)
- First posted
- 20 Aug 2018 (actual)
- Results
- Posted 26 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Avelumab and binimetinib | Experimental | Drug: Avelumab, Drug: BinimetinibOpen label |
| Avelumab, binimetinib and talazoparib | Experimental | Drug: Avelumab, Drug: Binimetinib, Drug: TalazoparibOpen label |
| Binimetinib and talazoparib. | Experimental | Drug: Binimetinib, Drug: TalazoparibOpen label. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid tumors that are not amenable for treatment with curative intent as follows:
- 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.
Key exclusion criteria (17 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AvelumabAlso: MSB0010718CIV treatment | Drug | Avelumab and binimetinib, Avelumab, binimetinib and talazoparib |
| BinimetinibAlso: MEK162, ARRY-438162Oral treatment | Drug | Avelumab and binimetinib, Avelumab, binimetinib and talazoparib, Binimetinib and talazoparib. |
| TalazoparibAlso: MDV3800, BMN 673Oral treatment | Drug | Avelumab, binimetinib and talazoparib, Binimetinib and talazoparib. |
Primary outcome
Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b
Time frame: 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.
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).
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.
16 secondary outcomes
Number of Participants With Adverse Events During the On-Treatment Period
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
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
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)
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
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)
Predose Concentration During Multiple Dosing (Ctrough) for Avelumab
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.
Predose Concentration During Multiple Dosing (Ctrough) for Binimetinib
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
Predose Concentration During Multiple Dosing (Ctrough) for Talazoparib
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
Maximum Observed Plasma Concentration (Cmax) for Avelumab
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
Maximum Observed Plasma Concentration (Cmax) for Binimetinib
Time frame: Post dose on Day 1 and Day 8 of Cycle 1
Number of Participants With Anti-drug Antibody (ADA) Categories
Time frame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
Neutralizing Antibodies (nAb) Against Avelumab
Time frame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months
Percentage of Participants With Confirmed Objective Response (OR) in Phase 1b Based on Investigator Assessment (RECIST v1.1)
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).
Progression-Free Survival (PFS) Based on Investigator Assessment (RECIST v1.1) in Phase 1b
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).
Overall Survival (OS) in Phase 1b
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).
Time-to-Tumor Response (TTR) in Phase 1b
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).
Duration of Response (DR) in Phase 1b
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).
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.
Time frame: Baseline
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37379764Rodon Ahnert J, Tan DS, Garrido-Laguna I, Harb W, Bessudo A, Beck JT, Rottey S, Bahary N, Kotecki N, Zhu Z, Deng S, Kowalski K, Wei C, Pathan N, Laliberte RJ, Messersmith WA. Avelumab or talazoparib in combination with binimetinib in metastatic pancreatic ductal adenocarcinoma: dose-finding results from phase Ib of the JAVELIN PARP MEKi trial. ESMO Open. 2023 Aug;8(4):101584. doi: 10.1016/j.esmoop.2023.101584. Epub 2023 Jun 26.
- Derived from this study: PubMed 32379297Sun C, Fang Y, Labrie M, Li X, Mills GB. Systems approach to rational combination therapy: PARP inhibitors. Biochem Soc Trans. 2020 Jun 30;48(3):1101-1108. doi: 10.1042/BST20191092.
- To obtain contact information for a study center near you, click here.Link provided by the sponsor.
- Individual participant dataSharing planned: No. Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pfizer CT.gov Call Center study director
Pfizer
18 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Avelumab, Binimetinib and Talazoparib in people with Pancreatic Cancer, run by Pfizer at 18 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 26 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 18 sites in United States, Singapore, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Dose Limiting Toxicities (DLTs) During the Primary DLT Evaluation Period (Cycle 1) in Phase 1b (time frame: From date of first study treatment to day 28 of study treatment (Up to 28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03637491, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jan 2022.