Clinical Trials /

High Dose IL-2 in Combination With Anti-PD-1 to Overcome Anti-PD-1 Resistance in Metastatic Melanoma and Renal Cell Carcinoma

NCT03991130

Description:

The primary objective of this single arm phase 2 trial is to assess the response rate [complete response (CR) + partial response (PR)] of combined nivolumab and HD IL-2 in subjects with metastatic melanoma and renal cell carcinoma. Response will be performed after each course of nivolumab and IL-2 using RECIST 1.1. Patients will be treated for one course past best response for a maximum of 3 courses.

Related Conditions:
  • Melanoma
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: High Dose IL-2 in Combination With Anti-PD-1 to Overcome Anti-PD-1 Resistance in Metastatic Melanoma and Renal Cell Carcinoma
  • Official Title: High Dose IL-2 in Combination With Anti-PD-1 to Overcome Anti-PD-1 Resistance in Metastatic Melanoma and Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: UCSD IIT HD IL-2
  • NCT ID: NCT03991130

Conditions

  • Melanoma Stage Iv
  • Renal Cell Carcinoma, Metastatic

Interventions

DrugSynonymsArms
IL-2 and NivolumabHigh Dose IL-2, Anti-PD-1High Dose IL-2 and Nivolumab

Purpose

The primary objective of this single arm phase 2 trial is to assess the response rate [complete response (CR) + partial response (PR)] of combined nivolumab and HD IL-2 in subjects with metastatic melanoma and renal cell carcinoma. Response will be performed after each course of nivolumab and IL-2 using RECIST 1.1. Patients will be treated for one course past best response for a maximum of 3 courses.

Detailed Description

      PrimaryObjective Determine the overall response rate (complete response and partial response)
      for patients receiving anti-PD-1 (nivolumab) and high dose IL-2 (HD IL-2) in subjects with
      metastatic melanoma or renal cell carcinoma who have previously progressed on anti-PD-1
      therapy. Response assessment will be performed using revised RECIST guideline (v 1.1).

      Secondary Objectives

        -  Characterize safety, tolerability and adverse effects (AE) profile of nivolumab with HD
           IL-2 in subjects with metastatic malignant melanoma or renal cell carcinoma

        -  Measure Progression-Free Survival (PFS) using RECIST 1.1 after completion of at least
           one course of therapy (2 doses of nivolumab, 2 cycles of HD IL-2) for subjects enrolled
           in the study.

      ExploratoryObjectives

        -  Correlate PD-L1 expression and tumor mutational burden (TMB) in archived diagnostic
           tumor tissue with best clinical response for subjects with metastatic melanoma and renal
           cell carcinoma

        -  Correlate myeloid-derived suppressor cells and T-cell subsets in peripheral blood during
           therapy with best clinical response (RECIST criteria) and treatment outcome in subjects
           with metastatic melanoma or renal cell carcinoma. Data will be collected prior to each
           treatment and after each course of treatment.

      Study Duration: 48 months Amount of Subjects: up to 25 subjects
    

Trial Arms

NameTypeDescriptionInterventions
High Dose IL-2 and NivolumabExperimental
  • IL-2 and Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  1. Patient has the ability to understand and the willingness to sign a written
             informed consent.

             2. Age ≥ 18 years at the time of consent. 3. At least 6 weeks of prior anti-PD-1
             therapy with documented clinical or radiographic progression. Last anti-PD-1 therapy
             must be within 6 months of enrollment.

             4. Histologically-confirmed diagnosis of unresectable stage III or metastatic (stage
             IV) melanoma or renal cell carcinoma 5. Measurable disease, defined as at least 1
             tumor that fulfills the criteria for a target lesion according to RECIST 1.1, and
             obtained by imaging within 28 days prior registration for protocol therapy.

             6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
             within 28 days prior to registration for protocol therapy.

             7. Adequate hepatic function within 28 days prior to registration for protocol therapy
             defined as meeting all of the following criteria: i. total bilirubin ≤ 1.5 × upper
             limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin
             levels > 1.5 x ULN (except in patients with Gilbert's syndrome who must have a total
             bilirubin less than 3.0 mg/dl.) ii. and aspartate aminotransferase (AST) ≤ 2.5 × ULN
             or ≤ 5 × ULN for subjects with known hepatic metastases iii. and alanine
             aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic
             metastases 8. Adequate renal function within 28 days prior to registration for
             protocol therapy defined by either of the following criteria: i. Serum creatinine ≤
             1.5 mg/dL ii. OR if serum creatinine > 1.5 mg/dL, estimated glomerular filtration rate
             (GFR) ≥ 50 mL/min 9. Adequate hematologic function within 28 days prior to
             registration for protocol therapy defined as meeting all of the following criteria: i.
             hemoglobin ≥ 9.0 g/dL ii. and absolute neutrophil count (ANC) ≥ 1000/L without the
             support of filgrastim iii. white blood cells (WBC) ≥ 3000/L iv. and platelet count ≥
             100 × 109/L 10. Adequate coagulation functioning within 28 days prior to registration
             for protocol therapy defined by either of the following criteria: i. INR < 1.5 × ULN
             ii. OR for subjects receiving warfarin or LMWH, the subjects must, in the
             investigator's opinion, be clinically stable with no evidence of active bleeding while
             receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if
             that is the goal of anticoagulant therapy.

             11. Adequate pulmonary and cardiac function for HD IL-2 (will be assessed clinically)
             12. Female subjects of childbearing potential must have confirmed negative urine or
             serum pregnancy test prior to drug administration and be willing to use two methods of
             birth control.

             13. Male subjects who are not surgically sterile (vasectomy) must agree to use an
             adequate method of contraception.

             14. Subject's toxicities from prior treatments must have recovered to a grade 1 or
             less (except for toxicities such as alopecia or vitiligo)

        Exclusion Criteria:

          1. Active infection requiring systemic therapy

          2. Women who are pregnant or breastfeeding.

          3. Second active malignancy within the past 5 years with the exception of localized basal
             or squamous cell skin cancer, in situ cervical or bladder cancer, or localized
             prostate cancer under active surveillance.

          4. Active symptomatic central nervous system (CNS) metastases. Prior treated metastases
             or asymptomatic metastases are allowed. Patient can receive radiation between
             treatments if deemed medically necessary.

          5. Surgery within 4 weeks prior to study treatment except for minor procedures.

          6. Uncontrolled or poorly-controlled hypertension (> 160 mmHg systolic or > 100 mmHg
             diastolic for > 4 weeks) despite standard medical management.

          7. Serious or non-healing wounds, ulcers, or bone fractures within 28 days prior to
             initiation of study treatment.

          8. Any arterial thromboembolic events, including but not limited to myocardial
             infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
             within 6 months prior to initiation of study treatment.

          9. Has any condition that, in the opinion of the investigator, might jeopardize the
             safety of the patient or interfere with protocol compliance.

         10. Has any mental or medical condition that prevents the patient from giving informed
             consent or participating in the trial.

         11. Known hypersensitivity to nivolumab or IL-2 or any of their components.

         12. Known history of active tuberculosis.

         13. Concurrent systemic steroid therapy with doses above physiologic level (more than 10
             mg of prednisone daily).

         14. Active autoimmune disease, including but not limited to myasthenia gravis, myositis,
             autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
             bowel disease, vascular thrombosis associated with anti-phospholipid syndrome,
             granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis, or glomerulonephritis requiring treatment. Patients
             cannot be on immunosuppressive medications other than physiologic replacement doses of
             prednisone (less than 10 mg per day at enrollment) or equivalent steroid. Asymptomatic
             patients or those stable on non-immunosuppressive medications are eligible.

         15. Treatment with any investigational agent within 21 days prior to initiation of study
             treatment and the subject must have recovered from the acute toxic effects of the
             regimen with the exception of prior anti-PD-1.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:3 years post treatment
Safety Issue:
Description:The primary endpoint will be the response rate [complete response (CR) and partial response (PR)] of combined therapy with nivolumab and HD IL-2 in metastatic melanoma and renal cell carcinoma and will be evaluated using revised RECIST 1.1. Response rate will be computed with associated 95% confidence intervals.

Secondary Outcome Measures

Measure:Drug Toxicity
Time Frame:After Initiation of a 35 day study treatment period up to 90 days following the last administration of study treatment
Safety Issue:
Description:Proportion of subjects with each grade of adverse events as defined by CTCAE v 5.0 will be computed. Toxicity will be reported in a tabular and descriptive manner.
Measure:Progression Free Survival
Time Frame:1 year +/- 3 months
Safety Issue:
Description:• Median PFS times will be calculate and PFS rate at 1 year +/- 3 months will be calculated with associated 95% confidence intervals based on the Kaplan-Meier method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mina Nikanjam

Trial Keywords

  • melanoma
  • renal cell carcinoma

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