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RecruitingLast updated: 23 February 2024

PRIME005: This study is investigating if treatment with chemotherapy enhances the immune response to immunotherapy in people with advanced melanoma who were previously unresponsive to treatmentPhase 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.

Clinical summary

Summary

This study will evaluate whether treatment with chemotherapy (azacitidine and carboplatin) enhances the immune response to immunotherapy rechallenge (with ipilimumab and nivolumab) in people with unresectable (which means unable to be removed by surgery) or metastatic melanoma who have been unresponsive to preivous CPI immunotherapy treatment that consisted of anti-PD1 and anti-CTLA4 antibodies.

It is hoped that data from thsi trial will help investigators understanding the tumour microenvironment of treatment-resistant metastatic melanoma.

What treatment is involved?

Eligible participants will receive the following treatment during Stage 1 of the study.

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. 

Ipilimumab and Nivolumab will continue every 6 weeks as maintenance therapy for 24 months or until disease progression, unless the treating clinician believes there is benefit with ocntinuing treatment. Tissue samples, disease progression rates and adverse events will be collected from participants.

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.

Ipilimumab (every 6 weeks) and Nivolumab (every 3 weeks) will continue as maintenance therapy for 24 months or until disease progression, unless the clinician believes that there is a clinical benefit to continue treatment.

Conditions

This trial is treating patients with unresectable or metastatic melanoma

Cancer

Skin Cancers Skin

Age

People18+

Phase

I/II

Trial Acronym

PRIME005

More information

Trial Identifiers

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Trial sponsor

Bristol Myers Squibb,University of Newcastle

Scientific Title

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.

Eligibility

Inclusion

- 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:
1. 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)
2. 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

 

- 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.
- History of immune-related toxicity to previous CPI immunotherapy is not an exclusion criteria provided patients do not have persisting/ active toxicities that are uncontrolled and clinically relevant at the time of enrolment and at the discretion of the investigator.

Inclusion

  • You are able to swallow medication by mouth.
  • You have had treatment but your cancer has gotten worse or has not responded to the treatment you have been given.
  • Your cancer has not spread to other parts of the body.
  • but it is not possible to perform surgery to remove it.
  • Your cancer has spread to other parts of the body.

Exclusion

  • You have been diagnosed with a prior or secondary type of cancer.
  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.
  • You have previously been treated (or are currently being treated) on a clinical trial.
Message

Clinical trials have complex eligibility criteria.

Ask your doctor if this trial could be right for you.

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