Metastatic Pancreatic Cancer
Conditions
Keywords
Pancreas cancer, Veliparib, oxaliplatin
Brief summary
People are being asked to participate in this study who have metastatic pancreatic cancer (cancer that has spread to other parts of the body). The purpose of this study is to test the efficacy (effectiveness) of a new combination of drugs, ABT-888 and mFOLFOX-6 (modified 5-Fluorouracil and Oxaliplatin) for patients with metastatic pancreatic cancer. ABT-888 inhibits an enzyme called PARP which helps to fix damaged DNA. By inhibiting this enzyme, ABT-888 prevents cancer cells from repairing the damage caused by the mFOLFOX-6, and will hopefully increase the killing of cancer cells, thus decreasing the tumors in your body.
Detailed description
This is a single arm, open-label Phase I/II study to evaluate the clinical activity of the novel inhibitor of Poly(ADP-ribose) polymerase (PARP), ABT-888 with modified FOLFOX-6 (5-Fluorouracil plus oxaliplatin) in patients with metastatic pancreatic cancer.
Interventions
Sponsors
Abbott
Georgetown University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven pancreatic adenocarcinoma with measurable disease * A known BRCA-associate genetic mutation OR family history suggesting of a breast or ovarian cancer syndrome, as defined by one or more of the following: * Personal or known family history of a deleterious (or indeterminate) mutation in the BRCA1, BRCA2, PALBB2, or one of the FANC genes. * Personal history of breast cancer and one or more of the following: * Diagnosed ≤ 45 years old * Diagnosed at any age with ≥1 1st, 2nd, or 3rd degree relative with breast cancer ≤ 50 years old and/or ≥1st, 2nd, or 3rd relative with epithelial ovarian cancer at any age * Two primary breast cancer with the first diagnosed at ≤ 50 years old * Diagnosed ≤ 60 years old with triple negative breast cancer * Diagnosed at any age with ≥2 1st, 2nd, or 3rd degree relatives with breast cancer at any age * Diagnosed at any age with ≥2 1st, 2nd, or 3rd degree relatives with pancreatic cancer or aggressive prostate cancer (Gleason score ≥7) at any age * 1st, 2nd, or 3rd degree male relative with breast cancer * Ashkenazi Jewish descent * Personal history of epithelial ovarian cancer * Personal history of male breast cancer * Personal history of pancreatic cancer and ≥2 1st, 2nd, or 3rd degree relatives with breast, epitherlial ovarian, pancreatic, or aggressive prostate cancer (Gleason score ≥7) at any age * Age \>= 18 years * ECOG performance status 0-2 * Subjects with no brain metastases or a history of previously treated brain metastases who have been treated with surgery or stereotactic radiosurgery at least 4 weeks prior to enrollment and have a baseline MRI that shows no evidence of intercranial disease and have not had treatment with steroids within 1 week of study enrollment. * Subjects may have received any number of prior therapies except prior therapy with a PARP inhibitor * At least 14 days must have passed since all prior anti-cancer therapy * At least 28 days must have passed since any prior antibody-based therapies * At least 28 days must have passed since any prior investigational agent * All patients must have completely recovered from all transient side effects related to prior therapies and any side effects that are expected to be more durable or permanent must have resolved to Grade 1 * Adequate hepatic, bone marrow and renal function * Partial thromboplastin time must be \</= 2 X upper limit of institution's normal range and INR \< 2. Subjects on an anticoagulant must have a PTT \</= 5 X upper limit of institution's normal range and INR \< 5. * Life expectancy \> 12 weeks * Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment * Subject must be capable of understanding and complying with parameters as outlined in protocol and able to sign and date the informed consent form * Patients must have fully recovered from all effects of surgery.
Exclusion criteria
* Active severe infection, or known chronic infection with HIV, Hepatitis B virus or Hepatitis C virus * Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months * Life-threatening visceral disease or other severe concurrent disease * Women who are pregnant or breast-feeding * Anticipated survival under 3 months * The subject has had another active malignancy within the past 5 years except for cervical cancer in situ, in situ carcinoma of the bladder, or non-melanoma carcinoma of the skin. * Active uncontrolled infection * Symptomatic congestive heart failure * Unstable angina pectoris or cardiac arrhythmia * Psychiatric illness/ social situation that would limit compliance with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Dose Limiting Toxicities | 28 days | Protocol defined events that are definitely, possibly or probably related to one or both agents and have occurred in the first cycle of therapy. Applies only to patients in the Phase I portion of the study. |
| Phase II: Objective Response Rate (ORR) | 6 months | Number of Participants in Phase II with a Complete response and Partial response as determined by RECIST 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | 6 months | DCR is defined as the number of patients with a complete response, partial response, or stable disease at 6 months per Recist 1.1. |
| Progression Free Survival (PFS) | up to 114 months | PFS is defined as the number of days from enrollment to progression or death, whichever occurred first. |
| Overall Survival | up to 114 months | The number of days from enrollment until death or last contact. Patients who were alive at the time of analysis were censored at their last contact. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: ABT-888 40mg (Cohort 1) ABT-888 orally at 40mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6 with 5-FU bolus mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 400 mg/m2 IV bolus followed by 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 6 |
| Phase 1: ABT-888 60 mg (Cohort 2) ABT-888 orally at 60mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 3 |
| Phase 1: ABT-888 80 mg (Cohort 3) ABT-888 orally at 80mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 3 |
| Phase 1: ABT-888 100 mg (Cohort 4) ABT-888 orally at 100mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 3 |
| Phase 1: ABT-888 150 mg (Cohort 5) ABT-888 orally at 150mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 3 |
| Phase 1: ABT-888 200 mg (Cohort 6) ABT-888 orally at 200mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 7 |
| Phase 1: ABT-888 250 mg (Cohort 7) ABT-888 orally at 250mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 6 |
| Phase 2: ABT-888 atRecommended Phase 2 Dose (200mg) ABT-888 orally at 200mg twice a day for Days 1-7 of each 14-day cycle with mFOLFOX-6: Oxaliplatin 85 mg/M2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1; 5-FU 2400 mg/m2 IV continuous infusion over 46 hours Days 1-3 | 33 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 0 | 0 | 1 | 0 | 2 | 0 | 5 |
| Overall Study | Death | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 2 |
| Overall Study | Progression of Disease | 4 | 2 | 2 | 3 | 1 | 6 | 3 | 0 | 23 |
| Overall Study | Shifted | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase 1: ABT-888 250 mg (Cohort 7) | Total | Phase 2: ABT-888 atRecommended Phase 2 Dose (200mg) | Phase 1: ABT-888 40mg (Cohort 1) | Phase 1: ABT-888 60 mg (Cohort 2) | Phase 1: ABT-888 80 mg (Cohort 3) | Phase 1: ABT-888 100 mg (Cohort 4) | Phase 1: ABT-888 150 mg (Cohort 5) | Phase 1: ABT-888 200 mg (Cohort 6) |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 25 Participants | 13 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 39 Participants | 20 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 60 Participants | 30 Participants | 6 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 11 Participants | 7 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 49 Participants | 23 Participants | 6 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 27 Participants | 17 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 37 Participants | 16 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 5 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 | 6 / 6 | 30 / 33 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 4 / 7 | 32 / 33 |
| serious Total, serious adverse events | 3 / 6 | 1 / 3 | 0 / 3 | 0 / 3 | 2 / 3 | 0 / 7 | 3 / 6 | 12 / 33 |
Outcome results
Primary
Phase 1: Number of Dose Limiting Toxicities
Protocol defined events that are definitely, possibly or probably related to one or both agents and have occurred in the first cycle of therapy. Applies only to patients in the Phase I portion of the study.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: ABT-888 40mg (Cohort 1) | Phase 1: Number of Dose Limiting Toxicities | 3 Dose Limiting Toxicities |
| Phase 1: ABT-888 60 mg (Cohort 2) | Phase 1: Number of Dose Limiting Toxicities | 0 Dose Limiting Toxicities |
| Phase 1: ABT-888 80 mg (Cohort 3) | Phase 1: Number of Dose Limiting Toxicities | 0 Dose Limiting Toxicities |
| Phase 1: ABT-888 100 mg (Cohort 4) | Phase 1: Number of Dose Limiting Toxicities | 0 Dose Limiting Toxicities |
| Phase 1: ABT-888 150 mg (Cohort 5) | Phase 1: Number of Dose Limiting Toxicities | 0 Dose Limiting Toxicities |
| Phase 1: ABT-888 200 mg (Cohort 6) | Phase 1: Number of Dose Limiting Toxicities | 0 Dose Limiting Toxicities |
| Phase 1: ABT-888 250 mg (Cohort 7) | Phase 1: Number of Dose Limiting Toxicities | 4 Dose Limiting Toxicities |
Primary
Phase II: Objective Response Rate (ORR)
Number of Participants in Phase II with a Complete response and Partial response as determined by RECIST 1.1.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: ABT-888 40mg (Cohort 1) | Phase II: Objective Response Rate (ORR) | 4 Participants |
Secondary
Disease Control Rate (DCR)
DCR is defined as the number of patients with a complete response, partial response, or stable disease at 6 months per Recist 1.1.
Time frame: 6 months
Population: response-evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1: ABT-888 40mg (Cohort 1) | Disease Control Rate (DCR) | 1 Participants |
| Phase 1: ABT-888 60 mg (Cohort 2) | Disease Control Rate (DCR) | 0 Participants |
| Phase 1: ABT-888 80 mg (Cohort 3) | Disease Control Rate (DCR) | 0 Participants |
| Phase 1: ABT-888 100 mg (Cohort 4) | Disease Control Rate (DCR) | 0 Participants |
| Phase 1: ABT-888 150 mg (Cohort 5) | Disease Control Rate (DCR) | 1 Participants |
| Phase 1: ABT-888 200 mg (Cohort 6) | Disease Control Rate (DCR) | 1 Participants |
| Phase 1: ABT-888 250 mg (Cohort 7) | Disease Control Rate (DCR) | 0 Participants |
| Phase 2: ABT-888 at Recommended Phase 2 Dose (200mg) | Disease Control Rate (DCR) | 5 Participants |
Secondary
Overall Survival
The number of days from enrollment until death or last contact. Patients who were alive at the time of analysis were censored at their last contact.
Time frame: up to 114 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: ABT-888 40mg (Cohort 1) | Overall Survival | 153 days |
| Phase 1: ABT-888 60 mg (Cohort 2) | Overall Survival | 89 days |
| Phase 1: ABT-888 80 mg (Cohort 3) | Overall Survival | 325 days |
| Phase 1: ABT-888 100 mg (Cohort 4) | Overall Survival | 294 days |
| Phase 1: ABT-888 150 mg (Cohort 5) | Overall Survival | 211 days |
| Phase 1: ABT-888 200 mg (Cohort 6) | Overall Survival | 176 days |
| Phase 1: ABT-888 250 mg (Cohort 7) | Overall Survival | 145.5 days |
| Phase 2: ABT-888 at Recommended Phase 2 Dose (200mg) | Overall Survival | 260 days |
Secondary
Progression Free Survival (PFS)
PFS is defined as the number of days from enrollment to progression or death, whichever occurred first.
Time frame: up to 114 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: ABT-888 40mg (Cohort 1) | Progression Free Survival (PFS) | 126.5 days |
| Phase 1: ABT-888 60 mg (Cohort 2) | Progression Free Survival (PFS) | 49 days |
| Phase 1: ABT-888 80 mg (Cohort 3) | Progression Free Survival (PFS) | 159 days |
| Phase 1: ABT-888 100 mg (Cohort 4) | Progression Free Survival (PFS) | 77 days |
| Phase 1: ABT-888 150 mg (Cohort 5) | Progression Free Survival (PFS) | 132 days |
| Phase 1: ABT-888 200 mg (Cohort 6) | Progression Free Survival (PFS) | 148 days |
| Phase 1: ABT-888 250 mg (Cohort 7) | Progression Free Survival (PFS) | 60.5 days |
| Phase 2: ABT-888 at Recommended Phase 2 Dose (200mg) | Progression Free Survival (PFS) | 102 days |