Clinical Trials /

A Study of Nivolumab and Hydroxychloroquine or Nivolumab/Ipilimumab and Hydroxychloroquine in Advanced Melanoma

NCT04464759

Description:

This study will evaluate the safety, tolerability and efficacy (objective response rate) of using hydroxychloroquine (HCQ) in combination with nivolumab and ipilimumab or with nivolumab alone in subjects with advanced/metastatic melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study of Nivolumab and Hydroxychloroquine or Nivolumab/Ipilimumab and Hydroxychloroquine in Advanced Melanoma
  • Official Title: LIMIT Melanoma: (Lysosomal Inhibition + Melanoma ImmunoTherapy) A Phase 1/2 Open Label Trial of Nivolumab and Hydroxychloroquine or Nivolumab/Ipilimumab and Hydroxychloroquine in Patients With Advanced Melanoma

Clinical Trial IDs

  • ORG STUDY ID: UPCC 01620
  • SECONDARY ID: IRB#835033
  • NCT ID: NCT04464759

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
NivolumabOpdivo®Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)
HydroxychloroquinePlaquenilPhase 1a: Nivolumab and Hydroxychloroquine (HCQ)
IpilimumabYERVOY®Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)

Purpose

This study will evaluate the safety, tolerability and efficacy (objective response rate) of using hydroxychloroquine (HCQ) in combination with nivolumab and ipilimumab or with nivolumab alone in subjects with advanced/metastatic melanoma.

Detailed Description

      There are three parts to this Phase 1/2 study in subjects with advanced melanoma:

      Phase 1a will identify the MTD and preliminary safety of combination hydroxychloroquine and
      nivolumab therapy.

      Phase 1b will identify the MTD and preliminary safety of hydroxychloroquine administered in
      conjunction with nivolumab and ipilimumab therapy

      Phase 2 will assess the clinical efficacy of combination hydroxychloroquine and nivolumab
      therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)ExperimentalDose escalation: Dose Level 1: HCQ 400 mg orally every 12 hours and nivolumab 480 mg IV every 4 weeks Dose Level 2: HCQ 600 mg orally every 12 hours and nivolumab 480 mg IV every 4 weeks Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.
  • Nivolumab
  • Hydroxychloroquine
Phase 2: Nivolumab and Hydroxychloroquine (HCQ)ExperimentalHCQ 400-600 mg (maximum tolerated dose from Phase 1a) orally every 12 hours and nivolumab 480 mg IV every 4 weeks Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.
  • Nivolumab
  • Hydroxychloroquine
Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)ExperimentalHCQ 400-600 mg orally every 12 hours and nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg IV every 3 weeks x4 cycles Then 6 weeks after the last dose of ipilimumab/nivolumab begin maintenance nivolumab 480 mg IV every 4 weeks Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.
  • Nivolumab
  • Hydroxychloroquine
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histological or cytological evidence of melanoma, unresectable Stage III or Stage IV,
             any genotype, and any programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC)
             status

          -  Phase 1a: nivolumab + HCQ: any prior treatment, or treatment naïve

          -  Phase 2: nivolumab + HCQ:

          -  - - Cohort 2a: prior immunotherapy in the adjuvant or metastatic setting is required

          -  - - Cohort 2b: anti-PD-1 Ab-naïve, but may have received any prior other therapy

          -  Phase 1b nivolumab + ipilimumab + HCQ: anti-PD-1 refractory

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  At least one measurable site of disease by RECIST 1.1 criteria that has not been
             previously irradiated.

          -  Fresh or archived primary or metastatic tissue available for submission for
             correlative analyses

          -  Negative serum pregnancy test within 28 days prior to commencement of dosing in
             premenopausal women. Negative urine pregnancy test within 24 hours of starting
             treatment.

          -  Able to swallow and retain oral medication and no clinically significant
             gastrointestinal abnormalities that may alter absorption such as malabsorption
             syndrome or major resection of the stomach or bowels

          -  Adequate baseline organ function

        Exclusion Criteria:

          -  Known serious concurrent infection or medical illness, including psychiatric
             disorders, which would jeopardize the ability to receive the protocol treatment with
             reasonable safety.

          -  Pregnant or breast-feeding.

          -  Patients with brain metastases treated with whole brain radiation that have been
             stable for 2 months are eligible; patients with brain metastases treated with gamma
             knife or surgery are allowed to participate after 2 weeks have elapsed since their
             procedure. Subjects are excluded if they have leptomeningeal disease or metastases
             causing spinal cord compression that are symptomatic or untreated or not stable for
             greater than or equal to 3 months (documented by imaging) or requiring corticosteroids
             greater than 20 mg prednisone equivalent daily.

          -  Must have discontinued active immunotherapy, chemotherapy, or investigational
             anticancer therapy at least 4 weeks prior to entering the study and oral targeted
             therapy at least 2 weeks prior to entering the study.

          -  All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
             values listed in protocol eligibility) must be less than or equal to Grade 1 or
             irreversible (hypophysitis) according to the Common Terminology Criteria for Adverse
             Events version 5 at the time of starting treatment. Patients that are asymptomatic on
             low dose maintenance hormone replacement delivered at a stable dose for prior
             toxicities are eligible.

          -  Prior or concurrent cancer therapy. Active immunotherapy, chemotherapy, or
             investigational anticancer therapy within 4 weeks prior to entering the study or oral
             targeted therapy within 2 weeks prior to entering the study

          -  Phase 2 nivolumab + HCQ Cohort B: No prior immunotherapy is permitted

          -  Patients known to be experiencing an objective partial response to immunotherapy at
             the time of study enrollment.

          -  History of malignancy other than disease under study within 3 years of study
             enrollment EXCEPT: history of completely resected non-melanoma skin cancer, or history
             of indolent second malignancies are eligible.

          -  Diagnosis of severe autoimmune disease requiring immunosuppressive medications.
             Patients with adrenal insufficiency on replacement dose steroids are eligible.

          -  History of interstitial lung disease or chronic pneumonitis unrelated to prior
             immunotherapy. Prior interstitial pneumonitis related to immunotherapy that was
             completely treated with no need for ongoing clinical management is allowed.

          -  Due to risk of disease exacerbation patients with porphyria or psoriasis are
             ineligible unless the disease is well controlled and they are under the care of a
             specialist for the disorder who agrees to monitor the patient for exacerbations.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to study drug, or excipients or to dimethyl sulfoxide.

          -  Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e.
             phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of
             the start of the study treatment

          -  Current use of a prohibited medication as described in section on Potential for
             Drug-Drug Interaction.

          -  History or evidence of increased cardiovascular risk
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Maximum tolerated dose (MTD) - Number of Subjects with Dose-limiting Toxicities
Time Frame:From first dose of protocol treatment to 16 to 32 weeks
Safety Issue:
Description:To determine the MTD and preliminary safety of HCQ when administered in conjunction with one of the following treatments in patients with advanced melanoma: HCQ administered in combination with nivolumab; or HCQ administered in combination with nivolumab and ipilimumab followed by maintenance nivolumab

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:From start of treatment to first progression, death due to any cause or last patient contact alive and progression-free over 24 months
Safety Issue:
Description:The time from protocol treatment start to disease progression, death due to any cause, or last contact alive and progression-free over 24 months
Measure:1 year survival rate
Time Frame:From start of treatment to one year
Safety Issue:
Description:Percentage of subjects alive at one year from start of treatment

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ravi Amaravadi, MD

Last Updated

July 8, 2020