Adenocarcinoma of the Pancreas, Metastatic Pancreatic Cancer, Pancreatic Cancer
Conditions
Keywords
AMG 479, Gemcitabine, TR-2, IGF-1R, AMG 655, Pancreatic cancer, Adenocarcinoma of the Pancreas, Metastatic Pancreatic Cancer
Brief summary
This is a multi-center, 2-part study of AMG 655, AMG 479 or AMG 655-placebo plus gemcitabine as first-line treatment of subjects with metastatic pancreatic cancer. Part 1 is an open-label, dose-escalation phase 1b segment to determine the safety, tolerability and maximum tolerated dose of AMG 655 in combination with gemcitabine. Enrollment into part 1 of the study has been completed. Part 2 is a randomized, placebo-controlled phase 2 segment to estimate the efficacy as assessed by 6 month survival of AMG 655, AMG 479, or AMG 655-placebo in combination with gemcitabine. The phase 2 segment that will commence after dose selection in part 1. In part 2, subjects will be randomized 1:1:1 to AMG 655, AMG 479, or placebo in combination with gemcitabine.
Interventions
Sponsors
NantCell, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Untreated metastatic adenocarcinoma of the pancreas (AJCC Stage IV) * Subjects with unresectable pancreatic cancer who have had surgery are eligible if fully recovered and greater than 30 days have elapsed since the surgery. Subjects with a history of pancreatoduodenectomy are eligible provided that there is radiographically documented disease recurrence. * Men or women ≥ 18 years of age * Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 * Adequate hematologic, hepatic, renal and coagulation function * Amylase and lipase ≤ 2.0 x ULN * Adequately controlled type 1 or 2 diabetic subjects
Exclusion criteria
* Islet cell, acinar cell carcinoma, non-adenocarcinoma (eg, lymphoma, sarcoma, etc), adenocarcinoma originated from biliary tree or cystadenocarcinoma * Known central nervous system metastases * Uncontrolled cardiac disease or any other co-morbid disease that would increase the risk of toxicity * Adjuvant chemotherapy or chemoradiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs; Phase 1b Portion Only) | 28 days | The incidence of adverse events and clinical laboratory abnormalities defined as DLTs. A DLT was defined as any grade 3 or higher hematologic or non-hematologic toxicity related to any study treatment. |
| Six Month Overall Survival Rate (Phase 2 Portion Only) | 6 months | The proportion of subjects alive at 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From start of study treatment through up to 36 months | Overall survival was defined as the time from study day 1 (phase 1b portion) or randomization (phase 2 portion) to death for any cause. |
| Number of Subjects With an Adverse Event | From start of study treatment through up to 44 weeks | Graded Using the National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events(CTCAE) Version 3.0 |
| Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | From start of study treatment through up to 48 weeks | PK parameter of Cmax for AMG 655 (phase 1b and phase 2 portions) - pg 266, ganitumab (phase 2 portion only) - pg 270 , and gemcitabine (phase 1b portion only - pg 272) PK parameters |
| Objective Response Rate | From start of study treatment through up to 36 months | Objective response was defined as a tumor response assessment of either complete response or partial response per modified Response Evaluation Criteria in Solid Tumors \[RECIST\] and was determined only for subjects with measurable disease at baseline. Per RECIST: a complete response is the disappearance of all target lesions; a partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Duration of Response | From objective response through up to 36 months | Duration of response was the time from the first observation of an objective response to the subsequent time of disease progression (per modified RECIST or clinical progression, whichever came first) or death due to any cause. Objective response = a tumor response assessment of either complete response or partial response per modified Response Evaluation Criteria in Solid Tumors \[RECIST\]. Per RECIST: a complete response is the disappearance of all target lesions; a partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Incidence of Antibody Formation | From start of treatment up to 40 weeks | The incidence of antibody formation of anti-AMG 655 (phase 1b and phase 2 portions) or anti- ganitumab (phase 2 portion only) |
| Dose Intensity of Gemcitabine (Phase 2 Portion Only) | From start of study treatment through up to 40 weeks | Average Dose intensity of gemcitabine when combined with AMG 655, placebo or AMG 479 |
| Progression-free Survival (PFS) | From start of study treatment through up to 36 months | PFS was defined as the time from study day 1 (phase 1b portion) or randomization (phase 2 portion) to the first observation of disease progression per investigator review (as classified by modified RECIST or clinical progression, whichever occurred first) or death due to any cause, or censoring. Disease progression per RECIST is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b AMG 655 3mg/kg Subjects were treated with one of 2 dose levels of AMG 655 (3 mg/kg) with gemcitabine.
AMG 655: AMG 655 is a fully human monoclonal agonist antibody directed against TRAIL Receptor 2 (TR-2). | 6 |
| Phase 1b AMG 655 10mg/kg Subjects were treated with one of 2 dose levels of AMG 655 (10 mg/kg) with gemcitabine.
AMG 655: AMG 655 is a fully human monoclonal agonist antibody directed against TRAIL Receptor 2 (TR-2). | 7 |
| Phase 2 AMG 655 Subjects were treated with the dose of AMG 655 (10mg/kg) in combination with gemcitabine. Gemcitabine (1000 mg/m2) was administered by intravenous infusion on days 1, 8 and 15 of each 28 day cycle followed by the AMG 655 infusion on days 1 and 15 after completion of the gemcitabine infusion.
AMG 655: AMG 655 is a fully human monoclonal agonist antibody directed against TRAIL Receptor 2 (TR-2). | 41 |
| Phase 2 AMG 479 Subjects were treated with the dose of AMG 479 (12 mg/kg) in combination with gemcitabine. Gemcitabine (1000 mg/m2) was administered by intravenous infusion on days 1, 8 and 15 of each 28 day cycle followed by the AMG 479 infusion on days 1 and 15 after completion of the gemcitabine infusion.
AMG 479: AMG 479 is fully human monoclonal antagonist antibody targeted against insulin-like growth factor receptor type 1 (IGF-1R). | 42 |
| Phase 2 AMG 655-placebo Subjects were treated with the dose of AMG 655-placebo in combination with gemcitabine. Gemcitabine (1000 mg/m2) was administered by intravenous infusion on days 1, 8 and 15 of each 28 day cycle followed by the AMG 655-placebo infusion on days 1 and 15 after completion of the gemcitabine infusion.
Placebo: Inactive dummy of AMG 655. | 42 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 5 | 4 | 2 |
| Overall Study | Death | 0 | 0 | 1 | 2 | 2 |
| Overall Study | Disease progression | 5 | 6 | 27 | 22 | 31 |
| Overall Study | Ineligibility determined | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Never received IP | 0 | 0 | 0 | 2 | 2 |
| Overall Study | Other | 0 | 0 | 4 | 2 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Phase 1b AMG 655 10mg/kg | Phase 1b AMG 655 3mg/kg | Phase 2 AMG 655 | Phase 2 AMG 655-placebo | Phase 2 AMG 479 |
|---|---|---|---|---|---|---|
| Age, Continuous Phase 1b | 65.3 years STANDARD_DEVIATION 12.8 | 63.7 years STANDARD_DEVIATION 15.1 | 67.2 years STANDARD_DEVIATION 10.7 | — | — | — |
| Age, Continuous Phase 2 | 62.3 years STANDARD_DEVIATION 10 | — | — | 62.3 years STANDARD_DEVIATION 9.3 | 62.6 years STANDARD_DEVIATION 9.1 | 62.1 years STANDARD_DEVIATION 11.5 |
| Metastatic pancreatic cancer | 138 Participants | 7 Participants | 6 Participants | 41 Participants | 42 Participants | 42 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 1 Participants | 0 Participants | 3 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 0 Participants | 0 Participants | 5 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) White | 116 Participants | 6 Participants | 6 Participants | 32 Participants | 37 Participants | 35 Participants |
| Sex: Female, Male Female | 58 Participants | 4 Participants | 4 Participants | 17 Participants | 16 Participants | 17 Participants |
| Sex: Female, Male Male | 80 Participants | 3 Participants | 2 Participants | 24 Participants | 26 Participants | 25 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 | 5 / 6 | 7 / 7 | 32 / 41 | 28 / 42 | 33 / 42 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 41 / 41 | 39 / 40 | 40 / 40 |
| serious Total, serious adverse events | 4 / 6 | 4 / 7 | 23 / 41 | 21 / 40 | 20 / 40 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities (DLTs; Phase 1b Portion Only)
The incidence of adverse events and clinical laboratory abnormalities defined as DLTs. A DLT was defined as any grade 3 or higher hematologic or non-hematologic toxicity related to any study treatment.
Time frame: 28 days
Population: The DLT analysis set consisted of subjects in the phase 1b portion of the study only, who experienced at least 1 DLT in the first 28 days of treatment or received 2 doses of AMG 655, 3 infusions of gemcitabine in a 28 day cycle at doses not less than 750 mg/m2 and were followed for at least 28 days (with or without DLTs).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Number of Participants With Dose Limiting Toxicities (DLTs; Phase 1b Portion Only) | 0 Participants |
| Phase 1b AMG 655 10mg/kg | Number of Participants With Dose Limiting Toxicities (DLTs; Phase 1b Portion Only) | 0 Participants |
Primary
Six Month Overall Survival Rate (Phase 2 Portion Only)
The proportion of subjects alive at 6 months
Time frame: 6 months
Population: Full analysis (The full analysis set consisted of all randomized subjects in the phase 2 portion of the study, with subjects analyzed according to the randomized treatment.)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Six Month Overall Survival Rate (Phase 2 Portion Only) | 59.2 percentage of participants |
| Phase 1b AMG 655 10mg/kg | Six Month Overall Survival Rate (Phase 2 Portion Only) | 56.6 percentage of participants |
| Phase 2 AMG 655-placebo | Six Month Overall Survival Rate (Phase 2 Portion Only) | 49.5 percentage of participants |
Secondary
Dose Intensity of Gemcitabine (Phase 2 Portion Only)
Average Dose intensity of gemcitabine when combined with AMG 655, placebo or AMG 479
Time frame: From start of study treatment through up to 40 weeks
Population: The safety analysis set consisted of all subjects who received at least 1 dose of investigational product, with subjects analyzed according to the treatment received.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b AMG 655 3mg/kg | Dose Intensity of Gemcitabine (Phase 2 Portion Only) | 861.40 mg/m^2 /infusion | Standard Deviation 119.45 |
| Phase 1b AMG 655 10mg/kg | Dose Intensity of Gemcitabine (Phase 2 Portion Only) | 906.66 mg/m^2 /infusion | Standard Deviation 115.76 |
| Phase 2 AMG 655-placebo | Dose Intensity of Gemcitabine (Phase 2 Portion Only) | 936.29 mg/m^2 /infusion | Standard Deviation 79.58 |
Secondary
Duration of Response
Duration of response was the time from the first observation of an objective response to the subsequent time of disease progression (per modified RECIST or clinical progression, whichever came first) or death due to any cause. Objective response = a tumor response assessment of either complete response or partial response per modified Response Evaluation Criteria in Solid Tumors \[RECIST\]. Per RECIST: a complete response is the disappearance of all target lesions; a partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From objective response through up to 36 months
Population: Only subjects with a CR or PR were analyzed. Duration of response was only measured for Phase 2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 2 AMG 655-placebo | Duration of Response | 301 Days |
| Phase 2 AMG 479 | Duration of Response | 253 Days |
| Phase 2 AMG 655-placebo | Duration of Response | 116 Days |
Secondary
Incidence of Antibody Formation
The incidence of antibody formation of anti-AMG 655 (phase 1b and phase 2 portions) or anti- ganitumab (phase 2 portion only)
Time frame: From start of treatment up to 40 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Incidence of Antibody Formation | 0 Participants |
| Phase 1b AMG 655 10mg/kg | Incidence of Antibody Formation | 0 Participants |
| Phase 2 AMG 655-placebo | Incidence of Antibody Formation | 0 Participants |
| Phase 2 AMG 479 | Incidence of Antibody Formation | 0 Participants |
| Phase 2 AMG 655-placebo | Incidence of Antibody Formation | 0 Participants |
Secondary
Number of Subjects With an Adverse Event
Graded Using the National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events(CTCAE) Version 3.0
Time frame: From start of study treatment through up to 44 weeks
Population: The safety analysis set consisted of all subjects who received at least 1 dose of investigational product, with subjects analyzed according to the treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Number of Subjects With an Adverse Event | 6 Participants |
| Phase 1b AMG 655 10mg/kg | Number of Subjects With an Adverse Event | 7 Participants |
| Phase 2 AMG 655-placebo | Number of Subjects With an Adverse Event | 41 Participants |
| Phase 2 AMG 479 | Number of Subjects With an Adverse Event | 39 Participants |
| Phase 2 AMG 655-placebo | Number of Subjects With an Adverse Event | 40 Participants |
Secondary
Objective Response Rate
Objective response was defined as a tumor response assessment of either complete response or partial response per modified Response Evaluation Criteria in Solid Tumors \[RECIST\] and was determined only for subjects with measurable disease at baseline. Per RECIST: a complete response is the disappearance of all target lesions; a partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From start of study treatment through up to 36 months
Population: The Safety Analysis Set for Phase 1b (the safety analysis set consisted of all subjects who received at least 1 dose of investigational product, with subjects analyzed according to the treatment received), and the Full Analysis for Phase 2 (the full analysis set consisted of all randomized subjects in the phase 2 portion of the study, with subjects analyzed according to the randomized treatment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Objective Response Rate | 16.67 percentage of responders |
| Phase 1b AMG 655 10mg/kg | Objective Response Rate | 14.29 percentage of responders |
| Phase 2 AMG 655-placebo | Objective Response Rate | 2.63 percentage of responders |
| Phase 2 AMG 479 | Objective Response Rate | 10.26 percentage of responders |
| Phase 2 AMG 655-placebo | Objective Response Rate | 2.50 percentage of responders |
Secondary
Overall Survival
Overall survival was defined as the time from study day 1 (phase 1b portion) or randomization (phase 2 portion) to death for any cause.
Time frame: From start of study treatment through up to 36 months
Population: The Safety Analysis Set for Phase 1b (the safety analysis set consisted of all subjects who received at least 1 dose of investigational product, with subjects analyzed according to the treatment received), and the Full Analysis for Phase 2 (the full analysis set consisted of all randomized subjects in the phase 2 portion of the study, with subjects analyzed according to the randomized treatment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Overall Survival | 9.0 Months |
| Phase 1b AMG 655 10mg/kg | Overall Survival | 8.9 Months |
| Phase 2 AMG 655-placebo | Overall Survival | 7.5 Months |
| Phase 2 AMG 479 | Overall Survival | 8.7 Months |
| Phase 2 AMG 655-placebo | Overall Survival | 5.9 Months |
Secondary
Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine
PK parameter of Cmax for AMG 655 (phase 1b and phase 2 portions) - pg 266, ganitumab (phase 2 portion only) - pg 270 , and gemcitabine (phase 1b portion only - pg 272) PK parameters
Time frame: From start of study treatment through up to 48 weeks
Population: The pharmacokinetic analysis set consisted of all subjects who underwent blood sampling for pharmacokinetic evaluation during the study. Cmax for AMG 655 was not calculated for the Phase 2 AMG 479 group because they did not receive AMG 655. The CMAX for AMG479 was not calculated for Phase 1b groups or the Phase 2 AMG 655 groups because they did not receive AMG 479. CMAX of gemcitabine for day 1 and day 8 were only performed in Phase 1b per protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b AMG 655 3mg/kg | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for AMG 655 | 55.3 μg/mL | Standard Deviation 11.3 |
| Phase 1b AMG 655 3mg/kg | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for gemcitabine - Day 1 | 15.7 μg/mL | Standard Deviation 7.79 |
| Phase 1b AMG 655 3mg/kg | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for gemcitabine - Day 8 | 10.5 μg/mL | Standard Deviation 5.9 |
| Phase 1b AMG 655 10mg/kg | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for gemcitabine - Day 8 | 11.2 μg/mL | Standard Deviation 5.76 |
| Phase 1b AMG 655 10mg/kg | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for gemcitabine - Day 1 | 14.8 μg/mL | Standard Deviation 7.84 |
| Phase 1b AMG 655 10mg/kg | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for AMG 655 | 198 μg/mL | Standard Deviation 32.5 |
| Phase 2 AMG 655-placebo | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for AMG 655 | 198 μg/mL | Standard Deviation 52.7 |
| Phase 2 AMG 479 | Pharmacokinetics of AMG 655, Ganitumab, and Gemcitabine | Cmax for AMG 479 | 179 μg/mL | Standard Deviation 55.2 |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from study day 1 (phase 1b portion) or randomization (phase 2 portion) to the first observation of disease progression per investigator review (as classified by modified RECIST or clinical progression, whichever occurred first) or death due to any cause, or censoring. Disease progression per RECIST is defined as at least a 20% increase in the sum of diameters of target lesions in reference to the smallest sum on study and an absolute increase of at least 5 mm; the appearance of any new lesions is also considered progression.
Time frame: From start of study treatment through up to 36 months
Population: The Safety Analysis Set for Phase 1b (the safety analysis set consisted of all subjects who received at least 1 dose of investigational product, with subjects analyzed according to the treatment received), and the Full Analysis for Phase 2 (the full analysis set consisted of all randomized subjects in the phase 2 portion of the study, with subjects analyzed according to the randomized treatment)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b AMG 655 3mg/kg | Progression-free Survival (PFS) | 5.4 Months |
| Phase 1b AMG 655 10mg/kg | Progression-free Survival (PFS) | 3.5 Months |
| Phase 2 AMG 655-placebo | Progression-free Survival (PFS) | 3.9 Months |
| Phase 2 AMG 479 | Progression-free Survival (PFS) | 5.1 Months |
| Phase 2 AMG 655-placebo | Progression-free Survival (PFS) | 2.1 Months |