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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04464759
Recruitment Status : Not yet recruiting
First Posted : July 9, 2020
Last Update Posted : July 9, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Ravi Amaravadi, MD, Abramson Cancer Center of the University of Pennsylvania

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Nivolumab Drug: Hydroxychloroquine Drug: Ipilimumab Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 94 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : July 30, 2020
Estimated Primary Completion Date : July 30, 2023
Estimated Study Completion Date : October 30, 2023


Arm Intervention/treatment
Experimental: Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)

Dose 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.

Drug: Nivolumab
Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
Other Name: Opdivo®

Drug: Hydroxychloroquine
Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
Other Name: Plaquenil

Experimental: Phase 2: Nivolumab and Hydroxychloroquine (HCQ)

HCQ 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.

Drug: Nivolumab
Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
Other Name: Opdivo®

Drug: Hydroxychloroquine
Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
Other Name: Plaquenil

Experimental: Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)

HCQ 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.

Drug: Nivolumab
Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
Other Name: Opdivo®

Drug: Hydroxychloroquine
Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
Other Name: Plaquenil

Drug: Ipilimumab
Combination of nivolumab, hydroxychloroquine and ipilimumab
Other Name: YERVOY®




Primary Outcome Measures :
  1. 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 ]

    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

  2. Phase 2: Objective Response Rate (ORR) [ Time Frame: 12 months ]
    To assess the ORR as measured by RECIST v1.1. in subjects with advanced melanoma


Secondary Outcome Measures :
  1. 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 ]
    The time from protocol treatment start to disease progression, death due to any cause, or last contact alive and progression-free over 24 months

  2. 1 year survival rate [ Time Frame: From start of treatment to one year ]
    Percentage of subjects alive at one year from start of treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04464759


Contacts
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Contact: Lydia Giles, BSN, RN 215-662-6389 lydia.giles@pennmedicine.upenn.edu
Contact: Mary Carberry 215-614-1813 mary.carberry@pennmedicine.upenn.edu

Locations
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United States, Pennsylvania
Abramson Cancer Center at University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Contact: Lydia Giles, BSN, RN    215-662-6389    lydia.giles@pennmedicine.upenn.edu   
Contact: Mary Carberry    215-614-1813    mary.carberry@pennmedicine.upenn.edu   
Sponsors and Collaborators
Ravi Amaravadi, MD
Bristol-Myers Squibb
Investigators
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Principal Investigator: Ravi Amaravadi, MD Abramson Cancer Center of the University of Pennsylvania
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Responsible Party: Ravi Amaravadi, MD, Associate Professor of Medicine, Abramson Cancer Center of the University of Pennsylvania
ClinicalTrials.gov Identifier: NCT04464759    
Other Study ID Numbers: UPCC 01620
IRB#835033 ( Other Identifier: University of Pennsylvania )
First Posted: July 9, 2020    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Hydroxychloroquine
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents