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Ipilimumab and Nivolumab for the Treatment of Stage III-IV Unresectable Metastatic Melanoma

Primary Purpose

Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ipilimumab
Nivolumab
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Clinical Stage III Cutaneous Melanoma AJCC v8

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age >=18 years
  • ALL patients with measurable disease
  • Dose De-escalation Cohort: Confirmed diagnosis of unresectable stage III or IV metastatic melanoma, meeting one of the following criteria:

    • Progressed after at least one line of Food and Drug Administration (FDA) approved therapy (either immune checkpoint inhibitor [ICI] or targeted therapy)
    • Recurrent disease following initial surgical resection (may or may not have received adjuvant therapy)
    • Newly diagnosed or recurrent in-transit metastatic melanoma (may or may not be treatment naive)
  • Hemoglobin >= 8.0 g/dL (obtained =< 15 days prior to registration)
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 15 days prior to registration)
  • Platelet count >= 75,000/mm^3 (obtained =< 15 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 15 days prior to registration)
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN (obtained =< 15 days prior to registration)
  • Serum creatinine =< 2.0 x ULN (obtained =< 15 days prior to registration)
  • Calculated creatinine clearance >= 40 ml/min using the Cockcroft-Gault formula (obtained =< 15 days prior to registration)
  • Prothrombin time (PT)/institutional normalized ratio (INR)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant therapy INR or aPTT is within target range of therapy (obtained =< 15 days prior to registration)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
  • Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only
  • Persons able to become pregnant OR able to father a child must be willing to use an adequate method of contraception while on treatment and for 180 days (6 months) after last treatment dose on this study
  • Provide written informed consent
  • Patients enrolling in Rochester, Minnesota (MN), ONLY: Willingness to provide mandatory blood specimens for correlative research
  • Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)

Exclusion Criteria:

  • Metastatic sites that drain lymphatic fluid into nodal beds which are not amenable to lymphatic infusion

    • Sites of metastases limited only to the head and neck
    • Sites of metastatic disease limited to the lungs and/or hilar lymph nodes
  • Metastatic uveal melanoma
  • Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

    • Pregnant persons
    • Nursing persons
    • Persons of childbearing potential who are unwilling to employ adequate contraception
    • Persons expecting to conceive or father children during the study or within 180 days (6 months) after the last treatment on this study
  • Active central nervous system (CNS) metastases not previously treated

    • NOTE: patients with history of previously treated CNS metastases, not demonstrating evidence of progression for at least 12 weeks will be allowed
    • NOTE: patients with leptomeningeal metastases are not eligible
  • Any of the following prior therapies:

    • Allogeneic hematopoietic stem cell transplantation (HSCT)
    • Solid organ transplantation
  • Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy.

    • NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Active autoimmune disease requiring systemic treatment < 2 years prior to registration, documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents with use of disease modifying agents, corticosteroids or immunosuppressive drugs. NOTE: Exceptions are allowed for the following conditions:

    • Vitiligo
    • Resolved childhood asthma/atopy
    • Intermittent use of bronchodilators or inhaled steroids
    • Daily steroids at dose of =< 10 mg of prednisone (or equivalent)
    • Local steroid injections
    • Stable hypothyroidism on replacement therapy
    • Stable diabetes mellitus on therapy (with or without insulin)
    • Sjogren's syndrome
    • Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) which is not considered a form of systemic treatment and is allowed
  • Uncontrolled intercurrent illness including, but not limited to:

    • Ongoing or active infection requiring systemic therapy
    • Interstitial lung disease
    • Serious, chronic gastrointestinal conditions associated with diarrhea (e.g., Crohn's disease or others)
    • Known history of hepatitis B (i.e., known positive hepatitis B virus [HBV] surface antigen [HBsAg] reactive)
    • Known active hepatitis C (i.e., positive for hepatitis C virus [HCV] ribonucleic acid [RNA] detected by polymerase chain reaction [PCR])
    • Known active tuberculosis (TB)
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Unstable cardiac arrhythmia or
    • Psychiatric illness/social situations that would limit compliance with study requirements (e.g., known substance abuse)
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • History of severe hypersensitivity reactions to other monoclonal antibodies or known hypersensitivity to the study intervention or its excipients, indocyanine green (ICG) dye or iodine
  • Prior history of grade 4 immune related adverse event (irAE) with prior intracavernosal injection (ICI) therapy or failure to recover (< grade 1) from immune-related adverse event(s) from prior ICI therapy
  • Any of the following therapies prior to registration:

    • Chemotherapy =< 28 days
    • Immunotherapy =< 28 days
    • Targeted therapies (e.g., dabrafenib) =< 21 days
    • Other investigational agents =< 28 days
    • Radiation therapy =< 14 days
    • Minor surgical or interventional procedure =< 7 days
    • Major surgical procedure =< 21 days

Sites / Locations

  • Mayo Clinic in RochesterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ipilimumab, nivolumab)

Arm Description

Patients receive ipilimumab via DoseConnect on day 1 of cycle 1 and via IV over 30 minutes on day 1 of cycles 2-4. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of ipilimumab administration via the DoseConnect device in combination with nivolumab
Incidence of adverse events
The maximum grade of each type of adverse event will be recorded for each patient. For each adverse event reported by dose level, the percentage of patients developing any degree of that adverse event as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
Progression-free survival
Will be estimated using the Kaplan-Meier method.
Overall survival
Will be estimated using the Kaplan-Meier method.

Secondary Outcome Measures

Full Information

First Posted
July 8, 2021
Last Updated
July 5, 2023
Sponsor
Mayo Clinic
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1. Study Identification

Unique Protocol Identification Number
NCT04967196
Brief Title
Ipilimumab and Nivolumab for the Treatment of Stage III-IV Unresectable Metastatic Melanoma
Official Title
Phase 1 Study of the Administration of Ipilimumab Intra-Lymphatically Using the Sofusa® DoseConnect™ DEVICE With Nivolumab Administered IV in Patients With Metastatic Melanoma
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 16, 2021 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
July 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mayo Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial identifies the best dose of ipilimumab that can be administered through the DoseConnect device followed by nivolumab in treating patients with stage III-IV melanoma that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Detailed Description
PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) of ipilimumab that can be administered through the DoseConnect device followed 30 minutes later by nivolumab intravenously (IV) on day 1 of a 21-day cycle in patients with metastatic melanoma. (Dose-De-escalation Cohort) SECONDARY OBJECTIVE: I. To assess the pharmacokinetics of ipilimumab administered using the DoseConnect followed 30 minutes later by nivolumab IV in patients with metastatic melanoma demonstrating in-transit metastases. (Dose De-escalation Cohort) CORRELATIVE OBJECTIVE: I. To assess the changes in immunologic profile after one cycle of ipilimumab administered using the DoseConnect followed 30 minutes later by nivolumab IV. (Dose-De-escalation Cohort) OUTLINE: Patients receive ipilimumab via DoseConnect on day 1 of cycle 1 and via IV over 30 minutes on day 1 of cycles 2-4. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 4 months until disease progression, and then every 6 months for up to 2 years after registration.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma, Unresectable Melanoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (ipilimumab, nivolumab)
Arm Type
Experimental
Arm Description
Patients receive ipilimumab via DoseConnect on day 1 of cycle 1 and via IV over 30 minutes on day 1 of cycles 2-4. Patients also receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Intervention Type
Biological
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, Ipilimumab Biosimilar CS1002, MDX-010, MDX-CTLA4, Yervoy
Intervention Description
Given via DoseConnect device or IV
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum tolerated dose of ipilimumab administration via the DoseConnect device in combination with nivolumab
Time Frame
Up to 21 days
Title
Incidence of adverse events
Description
The maximum grade of each type of adverse event will be recorded for each patient. For each adverse event reported by dose level, the percentage of patients developing any degree of that adverse event as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
Time Frame
Up to 21 days
Title
Progression-free survival
Description
Will be estimated using the Kaplan-Meier method.
Time Frame
Time from study entry to the documentation of disease progression, assessed up to 2 years
Title
Overall survival
Description
Will be estimated using the Kaplan-Meier method.
Time Frame
Time from study entry to death, assessed up to 2 years
Other Pre-specified Outcome Measures:
Title
Immune parameter analysis
Description
For each individual, a time series plot of the fold increase in a given immune parameter from pre-treatment levels will be constructed to visual inspect for trends. An immune response in a given parameter will be defined as a two-fold or more increase from pre-treatment levels for those with detectable levels prior to treatment or a two-fold or more increase from the LLD for those with levels below the LLD prior to treatment. A 90% confidence interval will be constructed for the difference in the proportion of patients who have an immune response after cycle 1 (ipilimumab [IpI] -DoseConnect [DC]) and lose it after cycle 2 (IpI-intravenous [IV]) and the proportion of patients who do not have an immune response after Cycle 1 (IpI -DC) but do after cycle 2 (IpI-IV).
Time Frame
Up to 2 cycles (1 cycle = 21 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >=18 years Measurable disease as defined below: A non-nodal lesion is considered measurable if its longest diameter can be accurately measured as >= 2.0 cm with chest x-ray, or as >= 1.0 cm with computed tomography (CT) scan, CT component of a positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) A superficial non-nodal lesion is measurable if its longest diameter is >= 1.0 cm in diameter as assessed using calipers (e.g., skin nodules) or imaging. In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. A malignant lymph node is considered measurable if its short axis is > 1.5 cm when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease. Histologically or cytologically confirmed diagnosis of unresectable stage III or IV metastatic melanoma, meeting one of the following criteria: Progressed after at least one line of FDA approved therapy (either immune checkpoint inhibitor [ICI] or targeted therapy) Recurrent disease following initial surgical resection (may or may not have received adjuvant therapy) Newly diagnosed or recurrent in-transit metastatic melanoma (may or may not be treatment naïve) Progressed on at least one line of therapy containing anti-PD-1, antiPD-L1, or a BRAF inhibitor Hemoglobin >= 8.0 g/dL (obtained =< 15 days prior to registration) Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 15 days prior to registration) Platelet count >= 75,000/mm^3 (obtained =< 15 days prior to registration) Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 15 days prior to registration) Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN (obtained =< 15 days prior to registration) Serum creatinine =< 2.0 x ULN (obtained =< 15 days prior to registration) Calculated creatinine clearance >= 40 ml/min using the Cockcroft-Gault formula (obtained =< 15 days prior to registration) Prothrombin time (PT)/institutional normalized ratio (INR)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant therapy INR or aPTT is within target range of therapy (obtained =< 15 days prior to registration) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only Persons able to become pregnant OR able to father a child must be willing to use an adequate method of contraception while on treatment and for 180 days (6 months) after last treatment dose on this study Provide written informed consent Patients enrolling in Rochester, Minnesota (MN), ONLY: Willingness to provide mandatory blood specimens for correlative research Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Exclusion Criteria: Metastatic sites that drain lymphatic fluid into nodal beds which are not amenable to lymphatic infusion Sites of metastases limited only to the head and neck Sites of metastatic disease limited to the lungs and/or hilar lymph nodes Metastatic uveal melanoma Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown: Pregnant persons Nursing persons Persons of childbearing potential who are unwilling to employ adequate contraception Persons expecting to conceive or father children during the study or within 180 days (6 months) after the last treatment on this study Active central nervous system (CNS) metastases not previously treated NOTE: patients with history of previously treated CNS metastases, not demonstrating evidence of progression for at least 12 weeks will be allowed NOTE: patients with leptomeningeal metastases are not eligible Any of the following prior therapies: Allogeneic hematopoietic stem cell transplantation (HSCT) Solid organ transplantation Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy. NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial Active autoimmune disease requiring systemic treatment < 2 years prior to registration, documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents with use of disease modifying agents, corticosteroids or immunosuppressive drugs. NOTE: Exceptions are allowed for the following conditions: Vitiligo Resolved childhood asthma/atopy Intermittent use of bronchodilators or inhaled steroids Daily steroids at dose of =< 10 mg of prednisone (or equivalent) Local steroid injections Stable hypothyroidism on replacement therapy Stable diabetes mellitus on therapy (with or without insulin) Sjogren's syndrome Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) which is not considered a form of systemic treatment and is allowed Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection requiring systemic therapy Interstitial lung disease Serious, chronic gastrointestinal conditions associated with diarrhea (e.g., Crohn's disease or others) Known history of hepatitis B (i.e., known positive hepatitis B virus [HBV] surface antigen [HBsAg] reactive) Known active hepatitis C (i.e., positive for hepatitis C virus [HCV] ribonucleic acid [RNA] detected by polymerase chain reaction [PCR]) Known active tuberculosis (TB) Symptomatic congestive heart failure Unstable angina pectoris Unstable cardiac arrhythmia or Psychiatric illness/social situations that would limit compliance with study requirements (e.g., known substance abuse) Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm History of severe hypersensitivity reactions to other monoclonal antibodies or known hypersensitivity to the study intervention or its excipients, indocyanine green (ICG) dye or iodine Prior history of grade 4 immune related adverse event (irAE) with prior intracavernosal injection (ICI) therapy or failure to recover (< grade 1) from immune-related adverse event(s) from prior ICI therapy Any of the following therapies prior to registration: Chemotherapy =< 28 days Immunotherapy =< 28 days Targeted therapies (e.g., dabrafenib) =< 21 days Other investigational agents =< 28 days Radiation therapy =< 14 days Minor surgical or interventional procedure =< 7 days Major surgical procedure =< 21 days
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anastasios Dimou
Organizational Affiliation
Mayo Clinic in Rochester
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Anastasios Dimou, M.D.

12. IPD Sharing Statement

Learn more about this trial

Ipilimumab and Nivolumab for the Treatment of Stage III-IV Unresectable Metastatic Melanoma

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