A Prospective Randomized, Open-label Phase 2 Study of Immune Checkpoint Inhibition, Nivolumab With or Without Ipilimumab in Combination With Radiation Therapy in Pretreated Patients With Metastatic Pancreatic Cancer or Biliary Tract Cancer.
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Metastatic Pancreatic Cancer
- Sponsor
- Herlev Hospital
- Enrollment
- 160
- Locations
- 1
- Primary Endpoint
- Clinical benefit rate (CBR)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a prospective, randomized, open-label phase 2 study in patients with metastatic PC or BTC refractory or intolerant to at least one line of prior systemic chemotherapy with gemcitabine or platinum-containing regimens to determine the efficacy and safety of nivolumab or nivolumab plus ipilimumab administered concurrently with high dose RT. Patients with metastatic PC or BTC who are feasible candidates for radiation and biopsy of primary and/or metastatic lesions will be included.
Detailed Description
This was a randomized phase II trial conducted at Herlev \& Gentofte Hospital. Patients were stratified according to PS and randomized into two arms (1:1) (Appendix Figure A1 and Data Supplement, online only). Patients received SBRT consisting of 15 Gy (day 1) to a single primary or metastatic lesion with 3 mg/kg of intravenous nivolumab (IV) on day 1 and every 2 weeks (q2w) (Arm A), or SBRT consisting of 15 Gy (day 1) with 3 mg/kg of IV nivolumab (day 1) q2w and 1 mg/kg of IV ipilimumab on day 1 and every 6 weeks (Arm B). A safety phase involving a run-in assessment of three patients from each arm (n = 6) was followed by the expansion phase. The patients were monitored for dose-limiting toxicities prior to the expansion. Treatment was continued for a maximum of 52 weeks or until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or clear clinical deterioration according to the investigator's judgment.
Investigators
Inna Chen, MD
Staff Specialist
Herlev Hospital
Eligibility Criteria
Inclusion Criteria
- •Signed informed consent
- •Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care
- •Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study
- •Histopathological confirmation of pancreatic adenocarcinoma or BTC prior to entering this study OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are consistent with a diagnosis of PC or BTC
- •At least one measurable primary in-situ (or locally-recurrent) or metastatic tumor must be present and, in the opinion of radiation oncologist, be amenable to RT as planned in the protocol and at least one additional metastatic tumor that will not undergo RT and which is measurable according to RECIST 1.1 criteria. Both lesions must be accessible for image-guided percutaneous biopsy
- •There is no upper limit on the number of prior chemotherapy regimens received. Patients must have received and failed or intolerance to at least one line of prior systemic chemotherapy with gemcitabine or platinum-containing regimens for unresectable and/or metastatic PC or BTC
- •Age \> 18 years and older
- •Life expectancy greater than 3 months
- •ECOG/WHO Performance Status (PS) 0-1
- •Patients must have normal organ and marrow function as defined below:
Exclusion Criteria
- •Malignant ascites that is clinically detectable by physical examination or is symptomatic. Evidence of radiographic ascites that is not clinically significant will not be exclusion criteria
- •Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- •No chemotherapy, radiotherapy, or major surgery within the last 2 weeks prior to entering the study
- •Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
- •Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
- •Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
- •Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
- •As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab- and ipilimumab containing regimen
- •Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- •Allergies and Adverse Drug Reaction
Arms & Interventions
Nivolumab & Radiotherapy
Patients will receive nivolumab 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT and then every 2 weeks (q2w), for a maximum of 52 weeks
Intervention: Nivolumab
Nivolumab & Radiotherapy
Patients will receive nivolumab 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT and then every 2 weeks (q2w), for a maximum of 52 weeks
Intervention: Radiotherapy
Nivolumab & Ipilimumab & Radiotherapy
Patients will receive nivolumab 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT. Thirty minutes after the completion of nivolumab infusion patients will receive ipilimumab 1 mg/kg over 90 minutes IV as an IV infusion. Nivolumab will be given every 2 weeks (q2w) and ipilimumab every 6 weeks (q6w), respectively for a maximum of 52 weeks
Intervention: Nivolumab
Nivolumab & Ipilimumab & Radiotherapy
Patients will receive nivolumab 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT. Thirty minutes after the completion of nivolumab infusion patients will receive ipilimumab 1 mg/kg over 90 minutes IV as an IV infusion. Nivolumab will be given every 2 weeks (q2w) and ipilimumab every 6 weeks (q6w), respectively for a maximum of 52 weeks
Intervention: Ipilimumab
Nivolumab & Ipilimumab & Radiotherapy
Patients will receive nivolumab 3 mg/kg over 60 minutes as an IV infusion on day 1 just after RT. Thirty minutes after the completion of nivolumab infusion patients will receive ipilimumab 1 mg/kg over 90 minutes IV as an IV infusion. Nivolumab will be given every 2 weeks (q2w) and ipilimumab every 6 weeks (q6w), respectively for a maximum of 52 weeks
Intervention: Radiotherapy
Outcomes
Primary Outcomes
Clinical benefit rate (CBR)
Time Frame: 6 months
Stable disease (SD) or complete response (CR) or partial response (PR)according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Secondary Outcomes
- Incidence of Treatment-Emergent Adverse Events [Safety](12 months)
- Overall response rate (ORR) according to RECIST 1.1(6 months)
- Progression free survival (PFS) per RECIST 1.1(6 months)
- Progression free survival (PFS) per modified irRC(6 months)
- Overall survival (OS) probability at 6 months(6 months)
- QoL(12 months)
- CBR(6 months)
- OS(12 months)
- Overall response rate (ORR) according to modified irRC(6 months)