Metastatic Pancreatic Ductal Adenocarcinoma
Conditions
Brief summary
There will be two phases to this study. The lead-in phase will evaluate the safety, pharmacokinetics, and define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with nab-paclitaxel and gemcitabine (nab-P + G) in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. The randomized treatment phase will evaluate the efficacy, safety, and tolerability of nab-P + G with either MMB administered at the MTD or placebo in adults with previously untreated metastatic pancreatic ductal adenocarcinoma. Participants will continue study treatment until disease progression, unacceptable toxicity, consent withdrawal, or participant's refusal of treatment. Following treatment, participants will be followed for safety for 30 days and for survival approximately every 3 months for up to 3 years.
Interventions
DRUGMomelotinib
Tablet (s) administered orally once or twice daily
Placebo to match momelotinib tablets administered orally once or twice daily
DRUGNab-paclitaxel
Intravenously administered over approximately 30-40 minutes or as per institutional standard of care on Days 1, 8, and 15 of each cycle
DRUGGemcitabine
Intravenously administered over approximately 30 minutes or as per institutional standard of care on Days 1, 8, and 15 of each cycle
Sponsors
Sierra Oncology LLC - a GSK company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Presence of metastatic pancreatic adenocarcinoma plus 1 of the following: * Histological diagnosis of pancreatic adenocarcinoma confirmed pathologically, OR * Pathologist confirmed histological/cytological diagnosis of adenocarcinoma consistent with pancreas origin in conjunction with either: * The presence of a mass in the pancreas, OR * A history of resected pancreatic adenocarcinoma * Measurable disease per RECIST v1.1 * Adequate organ function defined as follows: * Total bilirubin ≤ 1.25 x upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN * Absolute neutrophil count (ANC) \> 1500 cells/mm\^3, platelet \> 100,000 cells/mm\^3, hemoglobin \> 9 g/dL * Serum creatinine \< ULN OR calculated creatinine clearance (CrCl) of ≥ 60 ml/min * Eastern Cooperative Oncology Group (ECOG ) 0 or 1 * Modified Glasgow prognostic score (mGPS) of 1 or 2 at Screening (randomized phase only) Key
Exclusion criteria
* Neoadjuvant or adjuvant chemotherapy or chemoradiotherapy for pancreatic adenocarcinoma * Currently or previously treated with biologic, small molecule, immunotherapy, chemotherapy, or other agents for metastatic pancreatic carcinoma * Major surgery within 28 days of first dose of study drug * Minor surgical procedure(s) within 7 days of enrollment or not yet recovered from prior minor surgery (placement of central venous access device, fine needle aspiration, or endoscopic biliary stent ≥ 1 day before enrollment is acceptable) * Known positive status for HIV * Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C), or hepatitis B or C carrier * Peripheral neuropathy ≥ Grade 2 * Known or suspected brain or central nervous system metastases * Diagnosis of pancreatic islet neoplasm, acinar cell carcinoma, non-adenocarcinoma, adenocarcinoma originating from the biliary tree or cystadenocarcinoma * History of interstitial pneumonitis and/or require supplemental oxygen therapy * External biliary drain * Documented myocardial infarction or unstable/uncontrolled cardiac disease within 6 months of enrollment Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events | Up to 28 Days | Dose limiting toxicities were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Dose limiting toxicities referred to toxicities experienced during the first 28 days (Cycle 1) of treatment that were judged to be clinically significant and related to study treatment. No statistical analysis was planned or performed for this endpoint. |
| Randomized Treatment Phase: Overall Survival (OS) | Baseline up to the Date of Death or Censoring, up to 3 years | Overall survival was defined as the time interval from first dose date of MMB to death from any cause |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lead-In Phase: Overall Response Rate (ORR) | Baseline up to the Last Tumor Assessment Date, up to 3 years | The ORR was defined as the proportion of participants who achieved a best overall response (BOR) during MMB therapy of complete response (CR) or partial response (PR) as assessed by RECIST v1.1. |
| Lead-In Phase: Overall Survival (OS) | Baseline up to the Date of Death or Censoring, up to 3 years | Overall survival was defined as the time interval from first dose date of MMB to death from any cause |
| Randomized Treatment Phase: Overall Response Rate | Baseline up to the Last Tumor Assessment Date, up to 3 years | The ORR was defined as the proportion of subjects who achieved a best overall response (BOR) during MMB therapy of complete response (CR) or partial response (PR) |
| Randomized Treatment Phase: Progression-Free Survival (PFS) | Baseline up to the Date of Event or Censoring, up to 3 years | Progression-free survival was defined as the time interval from the first dose of MMB to the earlier of the first documentation of definitive disease progression or death from any cause |
| Lead-In Phase: Progression-Free Survival (PFS) | Baseline up to the Date of Event or Censoring, up to 3 years | Progression-free survival was defined as the time interval from the first dose of MMB to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression is progression based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria v1.1. Data from survival, non-progressing participants will be censored at the earliest of the time of initiation of anti-tumor therapy other than the study treatment or the last time that lack of definitive disease progression was objectively documented while on study. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States (US). The first participant was screened on 02 June 2014. The last study visit occurred on 10 April 2017.
Pre-assignment details
38 participants were screened. Data submitted represent analysis performed on data collected in the lead-in phase by the Study Termination Date, 10 April 2017. The study was discontinued before initiation of the randomized treatment phase, therefore no data were collected for the randomized treatment phase.
Participants by arm
| Arm | Count |
|---|---|
| MMB Dose Level 1 MMB 100 mg tablet once daily + nab-P+G (1000+1000 mg/m\^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle | 7 |
| MMB Dose Level 2 MMB 150 mg tablet once daily + nab-P+G (1000+1000 mg/m\^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle | 4 |
| MMB Dose Level 3 MMB 200 mg tablet once daily + nab-P+G (1000+1000 mg/m\^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle | 7 |
| MMB Dose Level 4 MMB 150 mg tablet twice daily + nab-P+G (1000+1000 mg/m\^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle | 3 |
| MMB Dose Level 5 MMB 200 mg tablet twice daily + nab-P+G (1000+1000 mg/m\^2) IV infusion on Days 1, 8, and 15 of each 28-day cycle | 4 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 4 | 3 | 6 | 0 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 1 | 0 | 1 | 1 | 1 |
| Overall Study | Withdrew Consent from study | 1 | 1 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | MMB Dose Level 1 | MMB Dose Level 2 | MMB Dose Level 3 | MMB Dose Level 4 | MMB Dose Level 5 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.9 years STANDARD_DEVIATION 12.32 | 63.5 years STANDARD_DEVIATION 12.12 | 64.7 years STANDARD_DEVIATION 8.79 | 52.0 years STANDARD_DEVIATION 5 | 59.0 years STANDARD_DEVIATION 9.13 | 60.7 years STANDARD_DEVIATION 10.21 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 6 Participants | 4 Participants | 7 Participants | 3 Participants | 4 Participants | 24 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 3 Participants | 6 Participants | 3 Participants | 4 Participants | 22 Participants |
| Region of Enrollment United States | 7 Participants | 4 Participants | 7 Participants | 3 Participants | 4 Participants | 25 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 5 Participants | 3 Participants | 3 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 7 | 3 / 4 | 6 / 7 | 0 / 3 | 3 / 4 |
| other Total, other adverse events | 7 / 7 | 4 / 4 | 7 / 7 | 3 / 3 | 4 / 4 |
| serious Total, serious adverse events | 4 / 7 | 3 / 7 | 5 / 7 | 2 / 3 | 4 / 4 |
Outcome results
Primary
Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events
Dose limiting toxicities were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Dose limiting toxicities referred to toxicities experienced during the first 28 days (Cycle 1) of treatment that were judged to be clinically significant and related to study treatment. No statistical analysis was planned or performed for this endpoint.
Time frame: Up to 28 Days
Population: DLT-Evaluable Analysis Set: participants in the Safety Analysis Set who completed all treatment and safety procedures through Day 28, inclusive, or experienced a DLT prior to Day 29. Participants in the DLT-Evaluable Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMB Dose Level 1 | Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events | 16.7 percentage of participants |
| MMB Dose Level 2 | Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events | 0 percentage of participants |
| MMB Dose Level 3 | Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events | 16.7 percentage of participants |
| MMB Dose Level 4 | Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events | 0 percentage of participants |
| MMB Dose Level 5 | Lead-In Phase: Percentage of Participants Experiencing Treatment-Emergent Dose Limiting Toxicity (DLT) Adverse Events | 0 percentage of participants |
Primary
Randomized Treatment Phase: Overall Survival (OS)
Overall survival was defined as the time interval from first dose date of MMB to death from any cause
Time frame: Baseline up to the Date of Death or Censoring, up to 3 years
Population: The study was discontinued before initiation of the randomized treatment phase.
Secondary
Lead-In Phase: Overall Response Rate (ORR)
The ORR was defined as the proportion of participants who achieved a best overall response (BOR) during MMB therapy of complete response (CR) or partial response (PR) as assessed by RECIST v1.1.
Time frame: Baseline up to the Last Tumor Assessment Date, up to 3 years
Population: All Enrolled Analysis Set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MMB Dose Level 1 | Lead-In Phase: Overall Response Rate (ORR) | Partial Response (PR) | 2 Participants |
| MMB Dose Level 1 | Lead-In Phase: Overall Response Rate (ORR) | Complete Response (CR) | 2 Participants |
| MMB Dose Level 2 | Lead-In Phase: Overall Response Rate (ORR) | Partial Response (PR) | 2 Participants |
| MMB Dose Level 2 | Lead-In Phase: Overall Response Rate (ORR) | Complete Response (CR) | 1 Participants |
| MMB Dose Level 3 | Lead-In Phase: Overall Response Rate (ORR) | Complete Response (CR) | 3 Participants |
| MMB Dose Level 3 | Lead-In Phase: Overall Response Rate (ORR) | Partial Response (PR) | 4 Participants |
| MMB Dose Level 4 | Lead-In Phase: Overall Response Rate (ORR) | Complete Response (CR) | 1 Participants |
| MMB Dose Level 4 | Lead-In Phase: Overall Response Rate (ORR) | Partial Response (PR) | 1 Participants |
| MMB Dose Level 5 | Lead-In Phase: Overall Response Rate (ORR) | Partial Response (PR) | 4 Participants |
| MMB Dose Level 5 | Lead-In Phase: Overall Response Rate (ORR) | Complete Response (CR) | 0 Participants |
Secondary
Lead-In Phase: Overall Survival (OS)
Overall survival was defined as the time interval from first dose date of MMB to death from any cause
Time frame: Baseline up to the Date of Death or Censoring, up to 3 years
Population: All Enrolled Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB Dose Level 1 | Lead-In Phase: Overall Survival (OS) | 12.4 Months |
| MMB Dose Level 2 | Lead-In Phase: Overall Survival (OS) | 5.1 Months |
| MMB Dose Level 3 | Lead-In Phase: Overall Survival (OS) | 8.7 Months |
| MMB Dose Level 4 | Lead-In Phase: Overall Survival (OS) | 5.6 Months |
| MMB Dose Level 5 | Lead-In Phase: Overall Survival (OS) | 7.1 Months |
Secondary
Lead-In Phase: Progression-Free Survival (PFS)
Progression-free survival was defined as the time interval from the first dose of MMB to the earlier of the first documentation of definitive disease progression or death from any cause. Definitive disease progression is progression based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria v1.1. Data from survival, non-progressing participants will be censored at the earliest of the time of initiation of anti-tumor therapy other than the study treatment or the last time that lack of definitive disease progression was objectively documented while on study.
Time frame: Baseline up to the Date of Event or Censoring, up to 3 years
Population: All Enrolled Analysis Set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MMB Dose Level 1 | Lead-In Phase: Progression-Free Survival (PFS) | 5.3 Months |
| MMB Dose Level 2 | Lead-In Phase: Progression-Free Survival (PFS) | 3.2 Months |
| MMB Dose Level 3 | Lead-In Phase: Progression-Free Survival (PFS) | 5.5 Months |
| MMB Dose Level 4 | Lead-In Phase: Progression-Free Survival (PFS) | 5.3 Months |
| MMB Dose Level 5 | Lead-In Phase: Progression-Free Survival (PFS) | 5.5 Months |
Secondary
Randomized Treatment Phase: Overall Response Rate
The ORR was defined as the proportion of subjects who achieved a best overall response (BOR) during MMB therapy of complete response (CR) or partial response (PR)
Time frame: Baseline up to the Last Tumor Assessment Date, up to 3 years
Population: The study was discontinued before initiation of the randomized treatment phase.
Secondary
Randomized Treatment Phase: Progression-Free Survival (PFS)
Progression-free survival was defined as the time interval from the first dose of MMB to the earlier of the first documentation of definitive disease progression or death from any cause
Time frame: Baseline up to the Date of Event or Censoring, up to 3 years
Population: The study was discontinued before initiation of the randomized treatment phase.