Phase Ib/II study of Azacitidine and Carboplatin priming for Ipilimumab and Nivolumab re-challenge in patients with advanced melanoma who are resistant to immunotherapy.
Phase Ib/II study of safety and clinical response to Azacitidine and Carboplatin priming for Ipilimumab and Nivolumab re-challenge in patients with advanced melanoma who are resistant to immunotherapy.
University of Newcastle
27 participants
Sep 13, 2021
Interventional
Conditions
Summary
This study, PRIME005, aims to investigate if treatment with oral Azacitidine and Carboplatin enhances the immune response to immunotherapy rechallenge with Ipilimumab and Nivolumab in patients previously unresponsive to treatment. Who is it for? You may be eligible for this study if you are aged 18 years or over and have unresectable or metastatic melanoma, with failed previous CPI immunotherapy with a combination of anti-PD1 and anti CTLA4 antibodies. Study details Participants will receive injection of Azacitidine and injection of Carboplatin for 2 cycles of treatment and addition of injection of Ipilimumab and Nivolumab over cycles 3 and 4 of treatment. Ipilimumab and Nivolumab will continue for 24 months or until disease progression, unless the treating clinician believes there is benefit with continuing treatment. Tissue samples, disease progression rates and adverse events will be collected from participants. It is hoped that data from this trial will help investigators understand the tumour microenvironment of treatment-resistant metastatic melanoma
Eligibility
Inclusion Criteria17
- Written informed consent to participate in the trial must be given according to ICH GCP and national/local regulations
- Male or Female subjects >= 18 years
- Unresectable or metastatic melanoma
- BRAF mutations status
- ECOG Performance status 0, 1, 2
- Must have failed previous CPI immunotherapy with a combination of anti-PD1 and anti CTLA4 antibodies according to immune response criteria in the BRAF wild type population
- OR
- Must have failed previous CPI immunotherapy with a combination of anti- PD1 and anti-CTLA4 antibodies according to immune response criteria as well as targeted therapy with BRAF and MEK inhibitors in the BRAF mutated population
- Patients with asymptomatic brain metastasis are eligible provided they have remained stable for 2 weeks prior to enrolment
- Patients with symptomatic brain metastases are eligible if their brain metastasis have been treated locally and if they are clinically stable for at least 2 weeks prior to enrolment- clinical stability of brain metastasis include the following two criteria:
- Minimally symptomatic, requiring the equivalent of <= 4 mg dexamethasone daily for at least 7 days prior to enrolment (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
- Patients that are borderline and not considered for further steroid taper at the start of study enrollment should be discussed with the overall principal investigator/medical monitor of the study before enrollment
- Adequate haematological function defined by absolute neutrophil count (ANC) >=1.0 x 10^9/L, platelet count >= 100 x 10^9/L, and haemoglobin >= 9g/dL (may have been transfused)
- Adequate hepatic function defined by a total bilirubin level >=1.5 x the upper limit of normal (ULN) range and AST and ALT levels >=3 x ULN for all subjects
- Adequate renal function defined by an estimated creatinine clearance of greater than 30mL/min according to the Cockcroft-Gault formula or local institutional method
- Disease status before first treatment should be documented by full CT scan of chest, abdomen and pelvis and MRI Brain.
- Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the first dose of study treatment
Exclusion Criteria11
- Uveal melanoma
- Prior organ transplantation, including allogeneic stem-cell transplantation
- Diagnosis of immunodeficiency
- Diagnosis of HIV; positive test for HBV surface antigen and/or confirmatory HCV RNA (if anti-HCV antibody tested positive) or any other significant acute or chronic infections
- Patient currently participating or receiving any study therapy or participating in a study of an investigational agent and received study therapy or used an investigational device within 3 weeks prior to the first dose of treatment
- Systemic steroid therapy >30mg/day prednisone equivalent or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment
- Active autoimmune disease that might deteriorate when receiving a CPI at the discretion of the investigator
- Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment or that are well controlled are eligible
- Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered for the purpose of hormonal replacement and at doses <= 30 mg or 30 mg equivalent prednisone per day
- Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
- Significant cardiovascular disease i.e., uncontrolled hypertension/angina/heart failure/arrhythmias, that require a significant change in systemic treatment to stabilize the cardiovascular disease.
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Interventions
Stage 1 of PRIME005 consisted of continuously administered cycles of the following: Cycles 1 & 2 - oral Azacitidine (200mg or 300mg) daily on days 1-14 and intravenous injection (IVI) Carboplatin AUC 4.5 on day 8 or day 15 over 6 weeks followed by Cycles 3 & 4 - oral Azacitidine (200mg or 300mg) daily on days 1-14 and IVI Carboplatin AUC 4.5 on day 8 or day 15 with Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) on day 15 for 6 weeks. Cycles 5 & 6 - Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) will be given in combination on day 1 of 21 day cycles. Maintenance Ipilimumab (every 6 weeks) and Nivolumab (every 3 weeks) will continue for 24 months or until disease progression by iRECIST unless the clinician believes that there is a clinical benefit to continue treatment beyond iRECIST progression and there is no unacceptable toxicity resulting from the treatment. Participants enrolled in Stage 1 were allocated by the Trial Coordinating Centre to epigenetic and chemotherapy priming at one of the following doses: Dose 1: 200mg oral Azacitidine daily D1-14 followed by Carboplatin AUC 4 IVI on Day 15 Dose 2: 300mg oral Azacitidine daily D1-14 followed by Carboplatin AUC 4 IVI on Day 8 Dose 3: 300mg oral Azacitidine daily D1-14 followed by Carboplatin AUC 4 IVI on Day 15 Stage 2 (Phase II): Participants will receive epigenetic and chemotherapy priming at the Recommended Phase 2 Dose (RP2D) from Stage 1 of 40mg/m2 azacitidine IVI Cycles 1 & 2 - Azacitidine (40mg/m2 intravenous injection (IVI)) daily on days 1-5 and IVI Carboplatin AUC 4.5 on day 8 over 6 weeks followed by Cycles 3 & 4 - Azacitidine (40mg/m2) daily on days 1-5 and IVI Carboplatin AUC 4.5 on day 8 with Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) on day 15 for 6 weeks. Cycles 5 & 6 - Ipilimumab injection (1mg/kg) and Nivolumab injection (360mg) will be given in combination on day 1 of 21 day cycles. Maintenance Ipilimumab (every 6 weeks) and Nivolumab (every 3 weeks) will continue for 24 months or until disease progression by iRECIST unless the clinician believes that there is a clinical benefit to continue treatment beyond iRECIST progression and there is no unacceptable toxicity resulting from the treatment.
Locations(2)
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ACTRN12621001155886