Biliary Tract Cancer
Conditions
Keywords
Metastatic, Platinum, Rucaparib, Nivolumab, PARP Inhibitor, Anti-PD-1 Antibody
Brief summary
Investigators hypothesize that following first-line platinum based chemotherapy, rucaparib in combination with nivolumab, will improve progression-free survival and overall survival in BTC patients.
Interventions
DRUGNivolumab
Nivolumab 240 mg IV days 1 and 15
DRUGRucaparib
Rucaparib 600 mg PO BID days 1-28
Sponsors
Dana-Farber Cancer Institute
Vanderbilt University Medical Center
University of Michigan Rogel Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a pathologically confirmed adenocarcinoma of the biliary tract (intra-hepatic, extra-hepatic (hilar, distal) or gall bladder) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are excluded. * Patients must have received 1st line platinum-based systemic chemotherapy for advanced BTC for 4-6 months without radiologic or clinical progression. Last systemic infusion of 1st line platinum-based therapy may not be more than 4 weeks from study informed consent. Prior peri-operative chemotherapy is permitted provided it was completed \> 6 months from start of platinum-based therapy for advanced disease. * Prior surgical resection, radiation, chemoembolization, radioembolization or other local ablative therapies are permitted if completed \> 4 weeks prior to enrollment AND if patient has recovered to \< 1 grade 1 toxicity. * Patients must have measurable disease (as per RECISTv1.1) in at least one site not previously treated with radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic site unless the patient has had complete response to 1st line platinum-based therapy. * Age≥18 years * Child-Pugh score of A or B7 (Scoring system used to assess the prognosis of chronic liver disease, mainly cirrhosis) * ECOG performance status of 0-1 (Eastern Cooperative Oncology Group scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 5 where 0 represents perfect health and 5 represents death.) * Ability to understand and willingness to sign IRB-approved informed consent * Available archived tissue (FFPE block or 20 unstained slides from prior core biopsy or surgery) * Must be able to tolerate CT and/or MRI with contrast * Adequate organ function obtained ≤ 2 weeks prior to registration
Exclusion criteria
* Diagnosis of immunodeficiency, or received systemic steroid therapy, or any other form of immunosuppressive therapy within 14 days prior to trial treatment. Short bursts of steroids of 5-7 days (for COPD exacerbation or other similar indication) are allowed. * Prior history of solid organ transplantation or brain metastasis (unless treated and stable) * Patients may not have undergone a major surgical procedure \< 4 weeks prior to registration * Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. Patients with history of malignancy are eligible provided primary treatment of that cancer was completed \> 1 year prior to registration and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy. * Ongoing active, uncontrolled infections (afebrile for \> 48 hours off antibiotics) * Have received a live vaccine within 30 days of planned start of the study therapy * Have a psychiatric illness, other significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements * Pregnant or breastfeeding since rucaparib and/or nivolumab may harm the fetus or child. All females of childbearing potential (not surgically sterilized and between menarche and 1-year post menopause) must have a blood or urine test to rule out pregnancy within 2 weeks prior to registration. * Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 6 months (for women) and 7 months (for men) following completion of study therapy * Participants with an active, known or suspected autoimmune disease which may affect vital organ function, or has/may require systemic immunosuppressive therapy for management. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. * Participants with a condition requiring systemic treatment with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses \>10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. * Patients may not have previously received anti PD1/PDL1 antibodies or PARP inhibitor for treatment of this cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Alive and Without Radiological or Clinical Progression at 4 Months | 4 months | Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. A clinical decision of progression by the site investigator will be based on the subject's overall clinical condition, including performance status, clinical symptoms, and laboratory data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients That Respond to Treatment | up 2 years after starting treatment, average of 4 months | The proportion of patients that display a partial response (PR) or complete response (CR) to treatment. Partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. Complete response is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. |
| Progression Free Survival (PFS) Time as Measured From Treatment Start | Up to 2 years | Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. |
| Progression Free Survival (PFS) Time as Measured From Start of 1st Line Platinum Therapy | Up to two years post treatment discontinuation | Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. |
| Overall Survival (OS) Time as Measured From Treatment Start | Up to two years post treatment discontinuation | — |
| Overall Survival (OS) Time as Measured From Start of 1st Line Platinum Therapy | Up to two years post treatment discontinuation | — |
Countries
United States
Participant flow
Pre-assignment details
One participant was enrolled, but never treated, as they did not meet lab requirements on C1D1
Participants by arm
| Arm | Count |
|---|---|
| Rucaparib and Nivolumab Rucaparib 600 mg PO BID days 1-28 Nivolumab 240 mg IV days 1 and 15
Rucaparib: Rucaparib 600 mg PO BID days 1-28
Nivolumab: Nivolumab 240 mg IV days 1 and 15 | 31 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 3 |
Baseline characteristics
| Characteristic | Rucaparib and Nivolumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 26 / 31 |
| other Total, other adverse events | 28 / 31 |
| serious Total, serious adverse events | 17 / 31 |
Outcome results
Primary
Proportion of Patients Alive and Without Radiological or Clinical Progression at 4 Months
Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions. A clinical decision of progression by the site investigator will be based on the subject's overall clinical condition, including performance status, clinical symptoms, and laboratory data.
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rucaparib and Nivolumab | Proportion of Patients Alive and Without Radiological or Clinical Progression at 4 Months | 54.8 percentage of participants |
Secondary
Overall Survival (OS) Time as Measured From Start of 1st Line Platinum Therapy
Time frame: Up to two years post treatment discontinuation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib and Nivolumab | Overall Survival (OS) Time as Measured From Start of 1st Line Platinum Therapy | 21.4 months |
Secondary
Overall Survival (OS) Time as Measured From Treatment Start
Time frame: Up to two years post treatment discontinuation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib and Nivolumab | Overall Survival (OS) Time as Measured From Treatment Start | 15.9 months |
Secondary
Progression Free Survival (PFS) Time as Measured From Start of 1st Line Platinum Therapy
Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.
Time frame: Up to two years post treatment discontinuation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib and Nivolumab | Progression Free Survival (PFS) Time as Measured From Start of 1st Line Platinum Therapy | 9.9 months |
Secondary
Progression Free Survival (PFS) Time as Measured From Treatment Start
Progressive disease is defined as at least a 20% increase in the sum of the longest diameter (LD) of target lesions (with a minimum absolute increase of 5 mm), taking as reference the smallest sum LD recorded since the treatment started, or the appearance of one or more new lesions.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rucaparib and Nivolumab | Progression Free Survival (PFS) Time as Measured From Treatment Start | 4.6 months |
Secondary
The Proportion of Patients That Respond to Treatment
The proportion of patients that display a partial response (PR) or complete response (CR) to treatment. Partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. Complete response is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions.
Time frame: up 2 years after starting treatment, average of 4 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rucaparib and Nivolumab | The Proportion of Patients That Respond to Treatment | 2 Participants |