<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04464759</url>
  </required_header>
  <id_info>
    <org_study_id>UPCC 01620</org_study_id>
    <secondary_id>IRB#835033</secondary_id>
    <nct_id>NCT04464759</nct_id>
  </id_info>
  <brief_title>A Study of Nivolumab and Hydroxychloroquine or Nivolumab/Ipilimumab and Hydroxychloroquine in Advanced Melanoma</brief_title>
  <acronym>LIMIT</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ravi Amaravadi, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Abramson Cancer Center at Penn Medicine</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate the safety, tolerability and efficacy (objective response rate) of&#xD;
      using hydroxychloroquine (HCQ) in combination with nivolumab and ipilimumab or with nivolumab&#xD;
      alone in subjects with advanced/metastatic melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There are three parts to this Phase 1/2 study in subjects with advanced melanoma:&#xD;
&#xD;
      Phase 1a will identify the MTD and preliminary safety of combination hydroxychloroquine and&#xD;
      nivolumab therapy.&#xD;
&#xD;
      Phase 1b will identify the MTD and preliminary safety of hydroxychloroquine administered in&#xD;
      conjunction with nivolumab and ipilimumab therapy&#xD;
&#xD;
      Phase 2 will assess the clinical efficacy of combination hydroxychloroquine and nivolumab&#xD;
      therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 21, 2020</start_date>
  <completion_date type="Anticipated">October 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">October 30, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase 1: Maximum tolerated dose (MTD) - Number of Subjects with Dose-limiting Toxicities</measure>
    <time_frame>From first dose of protocol treatment to 16 to 32 weeks</time_frame>
    <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:&#xD;
HCQ administered in combination with nivolumab; or&#xD;
HCQ administered in combination with nivolumab and ipilimumab followed by maintenance nivolumab</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2: Objective Response Rate (ORR)</measure>
    <time_frame>12 months</time_frame>
    <description>To assess the ORR as measured by RECIST v1.1. in subjects with advanced melanoma</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <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</time_frame>
    <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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>1 year survival rate</measure>
    <time_frame>From start of treatment to one year</time_frame>
    <description>Percentage of subjects alive at one year from start of treatment</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">94</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose escalation:&#xD;
Dose Level 1: HCQ 400 mg orally every 12 hours and nivolumab 480 mg IV every 4 weeks&#xD;
Dose Level 2: HCQ 600 mg orally every 12 hours and nivolumab 480 mg IV every 4 weeks&#xD;
Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase 2: Nivolumab and Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HCQ 400-600 mg (maximum tolerated dose from Phase 1a) orally every 12 hours and nivolumab 480 mg IV every 4 weeks&#xD;
Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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&#xD;
Then 6 weeks after the last dose of ipilimumab/nivolumab begin maintenance nivolumab 480 mg IV every 4 weeks&#xD;
Continue protocol treatment for up to 24 months until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-mandated study removal.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab</description>
    <arm_group_label>Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_label>Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_label>Phase 2: Nivolumab and Hydroxychloroquine (HCQ)</arm_group_label>
    <other_name>Opdivo®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydroxychloroquine</intervention_name>
    <description>Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab</description>
    <arm_group_label>Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_label>Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)</arm_group_label>
    <arm_group_label>Phase 2: Nivolumab and Hydroxychloroquine (HCQ)</arm_group_label>
    <other_name>Plaquenil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Combination of nivolumab, hydroxychloroquine and ipilimumab</description>
    <arm_group_label>Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)</arm_group_label>
    <other_name>YERVOY®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological or cytological evidence of melanoma, unresectable Stage III or Stage IV,&#xD;
             any genotype, and any programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC)&#xD;
             status&#xD;
&#xD;
          -  Phase 1a: nivolumab + HCQ: any prior treatment, or treatment naïve&#xD;
&#xD;
          -  Phase 2: nivolumab + HCQ:&#xD;
&#xD;
          -  - - Cohort 2a: prior immunotherapy in the adjuvant or metastatic setting is required&#xD;
&#xD;
          -  - - Cohort 2b: anti-PD-1 Ab-naïve, but may have received any prior other therapy&#xD;
&#xD;
          -  Phase 1b nivolumab + ipilimumab + HCQ: anti-PD-1 refractory&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1&#xD;
&#xD;
          -  At least one measurable site of disease by RECIST 1.1 criteria that has not been&#xD;
             previously irradiated.&#xD;
&#xD;
          -  Fresh or archived primary or metastatic tissue available for submission for&#xD;
             correlative analyses&#xD;
&#xD;
          -  Negative serum pregnancy test within 28 days prior to commencement of dosing in&#xD;
             premenopausal women. Negative urine pregnancy test within 24 hours of starting&#xD;
             treatment.&#xD;
&#xD;
          -  Able to swallow and retain oral medication and no clinically significant&#xD;
             gastrointestinal abnormalities that may alter absorption such as malabsorption&#xD;
             syndrome or major resection of the stomach or bowels&#xD;
&#xD;
          -  Adequate baseline organ function&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known serious concurrent infection or medical illness, including psychiatric&#xD;
             disorders, which would jeopardize the ability to receive the protocol treatment with&#xD;
             reasonable safety.&#xD;
&#xD;
          -  Pregnant or breast-feeding.&#xD;
&#xD;
          -  Patients with brain metastases treated with whole brain radiation that have been&#xD;
             stable for 2 months are eligible; patients with brain metastases treated with gamma&#xD;
             knife or surgery are allowed to participate after 2 weeks have elapsed since their&#xD;
             procedure. Subjects are excluded if they have leptomeningeal disease or metastases&#xD;
             causing spinal cord compression that are symptomatic or untreated or not stable for&#xD;
             greater than or equal to 3 months (documented by imaging) or requiring corticosteroids&#xD;
             greater than 20 mg prednisone equivalent daily.&#xD;
&#xD;
          -  Must have discontinued active immunotherapy, chemotherapy, or investigational&#xD;
             anticancer therapy at least 4 weeks prior to entering the study and oral targeted&#xD;
             therapy at least 2 weeks prior to entering the study.&#xD;
&#xD;
          -  All prior anti-cancer treatment-related toxicities (except alopecia and laboratory&#xD;
             values listed in protocol eligibility) must be less than or equal to Grade 1 or&#xD;
             irreversible (hypophysitis) according to the Common Terminology Criteria for Adverse&#xD;
             Events version 5 at the time of starting treatment. Patients that are asymptomatic on&#xD;
             low dose maintenance hormone replacement delivered at a stable dose for prior&#xD;
             toxicities are eligible.&#xD;
&#xD;
          -  Prior or concurrent cancer therapy. Active immunotherapy, chemotherapy, or&#xD;
             investigational anticancer therapy within 4 weeks prior to entering the study or oral&#xD;
             targeted therapy within 2 weeks prior to entering the study&#xD;
&#xD;
          -  Phase 2 nivolumab + HCQ Cohort B: No prior immunotherapy is permitted&#xD;
&#xD;
          -  Patients known to be experiencing an objective partial response to immunotherapy at&#xD;
             the time of study enrollment.&#xD;
&#xD;
          -  History of malignancy other than disease under study within 3 years of study&#xD;
             enrollment EXCEPT: history of completely resected non-melanoma skin cancer, or history&#xD;
             of indolent second malignancies are eligible.&#xD;
&#xD;
          -  Diagnosis of severe autoimmune disease requiring immunosuppressive medications.&#xD;
             Patients with adrenal insufficiency on replacement dose steroids are eligible.&#xD;
&#xD;
          -  History of interstitial lung disease or chronic pneumonitis unrelated to prior&#xD;
             immunotherapy. Prior interstitial pneumonitis related to immunotherapy that was&#xD;
             completely treated with no need for ongoing clinical management is allowed.&#xD;
&#xD;
          -  Due to risk of disease exacerbation patients with porphyria or psoriasis are&#xD;
             ineligible unless the disease is well controlled and they are under the care of a&#xD;
             specialist for the disorder who agrees to monitor the patient for exacerbations.&#xD;
&#xD;
          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to study drug, or excipients or to dimethyl sulfoxide.&#xD;
&#xD;
          -  Patients receiving cytochrome P450 enzyme-inducing anticonvulsant drugs (i.e.&#xD;
             phenytoin, carbamazepine, Phenobarbital, primidone or oxcarbazepine) within 4 weeks of&#xD;
             the start of the study treatment&#xD;
&#xD;
          -  Current use of a prohibited medication as described in section on Potential for&#xD;
             Drug-Drug Interaction.&#xD;
&#xD;
          -  History or evidence of increased cardiovascular risk&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ravi Amaravadi, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Abramson Cancer Center at Penn Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lydia Giles, BSN, RN</last_name>
    <phone>215-662-6389</phone>
    <email>lydia.giles@pennmedicine.upenn.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Mary Carberry</last_name>
    <phone>215-614-1813</phone>
    <email>mary.carberry@pennmedicine.upenn.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Abramson Cancer Center at University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lydia Giles, BSN, RN</last_name>
      <phone>215-662-6389</phone>
      <email>lydia.giles@pennmedicine.upenn.edu</email>
    </contact>
    <contact_backup>
      <last_name>Mary Carberry</last_name>
      <phone>215-614-1813</phone>
      <email>mary.carberry@pennmedicine.upenn.edu</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>December 8, 2022</last_update_submitted>
  <last_update_submitted_qc>December 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Abramson Cancer Center at Penn Medicine</investigator_affiliation>
    <investigator_full_name>Ravi Amaravadi, MD</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydroxychloroquine</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04464759
org study id: UPCC 01620
secondary id: IRB#835033
nct id: NCT04464759
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
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.
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.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
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
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
measure: Phase 2: Objective Response Rate (ORR)
time frame: 12 months
description: To assess the ORR as measured by RECIST v1.1. in subjects with advanced melanoma
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
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
description: Percentage of subjects alive at one year from start of treatment
arm group label: Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)
arm group type: Experimental
description: 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.
arm group label: Phase 2: Nivolumab and Hydroxychloroquine (HCQ)
arm group type: Experimental
description: 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.
arm group label: Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)
arm group type: Experimental
description: 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.
intervention type: Drug
intervention name: Nivolumab
description: Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
arm group label: Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)
arm group label: Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)
arm group label: Phase 2: Nivolumab and Hydroxychloroquine (HCQ)
other name: Opdivo®
intervention type: Drug
intervention name: Hydroxychloroquine
description: Combination of nivolumab and hydroxychloroquine OR nivolumab, hydroxychloroquine and ipilimumab
arm group label: Phase 1a: Nivolumab and Hydroxychloroquine (HCQ)
arm group label: Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)
arm group label: Phase 2: Nivolumab and Hydroxychloroquine (HCQ)
other name: Plaquenil
intervention type: Drug
intervention name: Ipilimumab
description: Combination of nivolumab, hydroxychloroquine and ipilimumab
arm group label: Phase 1b: Nivolumab + Ipilimumab +Hydroxychloroquine (HCQ)
other name: YERVOY®
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ravi Amaravadi, MD
role: Principal Investigator
affiliation: Abramson Cancer Center at Penn Medicine
last name: Lydia Giles, BSN, RN
phone: 215-662-6389
email: lydia.giles@pennmedicine.upenn.edu
last name: Mary Carberry
phone: 215-614-1813
email: mary.carberry@pennmedicine.upenn.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Abramson Cancer Center at Penn Medicine
investigator full name: Ravi Amaravadi, MD
investigator title: Associate Professor of Medicine
mesh term: Melanoma
mesh term: Hydroxychloroquine
mesh term: Nivolumab
mesh term: Ipilimumab