Phase 2 INSPIRE Trial: Ipilimumab With Nivolumab for Molecular- Selected Patients With Castration-resistant Prostate Cancer
Overview
- Phase
- Phase 2
- Intervention
- Ipilimumab
- Conditions
- Prostatic Neoplasms, Castration-Resistant
- Sponsor
- Radboud University Medical Center
- Enrollment
- 69
- Locations
- 1
- Primary Endpoint
- Efficacy endpoint: DCR
- Status
- Completed
- Last Updated
- 3 months ago
Overview
Brief Summary
The purpose of this study is to evaluate the effects of 4 cycles of combinatory immunotherapy (ipilimumab and nivolumab), followed by monotherapy nivolumab in participants with immunogenic metastatic castration-resistant prostate cancer.
Detailed Description
Following molecular characterization (next-generation sequencing) a total of 75 mCRPC patients with a putative immunogenic subtype will be included within the phase 2 INSPIRE trial. As treatment we will be utilizing a combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg for 4 doses, followed by nivolumab 480mg flat dose for up to one year. All participants will additionally undergo an on-trial metastatic tissue biopsy. Translational research will study immunological correlates and in-depth genomic/transcriptomic and multispectral immunohistochemical analyses of immune infiltrate.
Investigators
Eligibility Criteria
Inclusion Criteria
- •In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- •Written informed consent.
- •Histological diagnosis of adenocarcinoma of the prostate. Patients who have no histological diagnosis must be willing to undergo a biopsy to prove prostate adenocarcinoma.
- •Metastatic Castration-Resistant Prostate Cancer (mCRPC), metastatic disease defined either as measurable disease by RECIST1.1 criteria or presence of bone-metastatic disease evaluable per PCWG3 criteria. For cohort 1, measurable disease is compulsory.
- •An immunogenic phenotype, consisting of one of the next criteria: 1, mismatch repair deficiency and/or a high mutational burden of \>7 mutations per Mb (cluster A); 2, BRCA2 inactivation or BRCAness signature (cluster B); 3, a tandem duplication signature and/or CDK12 biallelic inactivation (cluster C)
- •Age ≥18 years.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-
- •PSA ≥ 2 ng/ml.
- •Documented willingness to use an effective means of contraception while participating in the study and for 7 months post last dose of treatment
- •Documented ongoing castrate serum testosterone \<50 ng/dL (\<2.0 nM).
Exclusion Criteria
- •A potential subject who meets any of the following criteria will be excluded from participation in this study:
- •Prior treatment with checkpoint immunotherapy (CTLA-4, or PD-1 and PD-L1 antagonists) for cohort
- •For cohort 2, patients may have prior treatment with monotherapy CTLA-4 or PD-1 or PD-L
- •Surgery or chemotherapy within 4 weeks prior to trial entry / randomisation into the study. Any other therapies for prostate cancer, other than GnRH analogue therapy and osteoporosis preventing agents, are not allowed.
- •Radiotherapy within 2 weeks prior to trial entry. Radiation-related side effects higher than grade 1, or above baseline.
- •Participation in another interventional clinical trial and any concurrent treatment with any investigational drug within 4 weeks prior to trial entry/randomisation.
- •History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumours, brain metastases, or alcoholism.
- •Untreated or symptomatic brain or leptomeningeal involvement.
- •Inadequate organ and bone marrow function as evidenced by:
- •hemoglobin \<6.2 mmol/L
Arms & Interventions
Treatment arm
Combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg, followed by nivolumab 480mg flat dose (Q4w) to up to one year. This regimen will be given to participants in both cohort 1 and 2.
Intervention: Ipilimumab
Treatment arm
Combinatory regimen of nivolumab 3mg/kg and ipilimumab 1mg/kg, followed by nivolumab 480mg flat dose (Q4w) to up to one year. This regimen will be given to participants in both cohort 1 and 2.
Intervention: Nivolumab
Outcomes
Primary Outcomes
Efficacy endpoint: DCR
Time Frame: At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49
For patients with RECIST1.1 evaluable disease this includes a change from baseline in tumour volume as measured by PR or CR by best ORR, or an SD, all lasting longer than 6mo, and the absence of clinical disease progression. In patients without RECIST1.1 evaluable disease, disease control is defined by the absence of new measurable lesions and unequivocal PD of non-target lesions on CT scan, the absence of bone progression as defined by the PCWG3 criteria, and the absence of clinical disease progression
Secondary Outcomes
- Efficacy endpoint: ORR(At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49)
- Safety endpoint: adverse effects(At inclusion, Weeks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, and 49, and at end of treatment (typically at one year, or earlier when treatment is stopped prematurely))
- Efficacy endpoint: rPFS(At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49)
- Efficacy endpoint: BRR(BRR at Week 13, PSA at inclusion, Weeks 1, 4, 7, 10, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49 and at end of treatment (typically one year, or earlier when treatment is stopped prematurely))
- Efficacy endpoint: OS(Follow-up of 1 year following trial discontinuation (onwards from the 30-day safety follow-up visit).)
- Efficacy in the BRCA, CDK12 and MSI/hTMB subgroups(At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49)
- Efficacy in the subgroup of patients with prior RT(At inclusion, Weeks 7, 17, 29, and 41, and 30 days after last dose given at week 49)