Clinical Trials /

A Study of APX005M in Combination With Nivolumab and Ipilimumab in Treatment Naïve Patients With Advanced Melanoma or Renal Cell Carcinoma (RCC)

NCT04495257

Description:

This study is a Phase 1, open-label, single institution, dose escalation and dose expansion study to evaluate the efficacy, safety, and tolerability of APX005M in combination with nivolumab and ipilimumab in patients with advanced melanoma and RCC.

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

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of APX005M in Combination With Nivolumab and Ipilimumab in Treatment Naïve Patients With Advanced Melanoma or Renal Cell Carcinoma (RCC)
  • Official Title: A Phase I Study of APX005M in Combination With Nivolumab and Ipilimumab in Treatment Naïve Patients With Advanced Melanoma or Renal Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: 2000026830
  • NCT ID: NCT04495257

Conditions

  • Advanced Melanoma
  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
NivolumabCohort Dose Level 1 (DL1)
IpilimumabCohort Dose Level 1 (DL1)
APX005MCohort Dose Level 1 (DL1)

Purpose

This study is a Phase 1, open-label, single institution, dose escalation and dose expansion study to evaluate the efficacy, safety, and tolerability of APX005M in combination with nivolumab and ipilimumab in patients with advanced melanoma and RCC.

Detailed Description

      This trial is a phase 1 study to evaluate the safety and tolerability of APX005M in
      combination with nivolumab and ipilimumab. The study will enroll patients with advanced solid
      tumors (melanoma, RCC) to determine the recommended phase II dosing (RP2D) of APX005M in
      combination with ipilimumab 1mg/kg and nivolumab 3 mg/kg (IPI1 NIVO3) every 3 weeks for four
      cycles followed by APX005M in combination with nivolumab 360mg every 3 weeks. APX005M will be
      administered at a dose of 0.1 mg/kg every 3 weeks in Dose Level 1 (DL1) and escalated to 0.3
      mg/kg every 3 weeks in Dose Level 2 (DL2) (Table 1). The IPI1 NIVO3 regimen is approved for
      patients with metastatic RCC.

      APX005M is a humanized IgG1 agonistic monoclonal antibody that binds CD40. Nivolumab is a
      humanized IgG4 monoclonal antibody directed against PD-1. Ipilimumab is a humanized IgG1κ
      monoclonal antibody directed against CTLA-4.

      Primary Objective

        -  To assess the safety and tolerability of APX005M in combination with nivolumab and
           ipilimumab

        -  To determine the recommended RP2D of APX005M in combination with nivolumab and
           ipilimumab in patients with unresectable metastatic melanoma or renal cell carcinoma.

      Secondary Objective

      • Determine rate and pattern of AEs in patients treated with APX005M in combination with
      nivolumab and ipilimumab
    

Trial Arms

NameTypeDescriptionInterventions
Cohort Dose Level 1 (DL1)ExperimentalDL1 will include ipilimumab at 1mg/kg and nivolumab at 3 mg/kg with APX005M of 0.1mg/kg for the induction phase. After 4 cycles, participants will be treated with 360mg of nivolumab and APX005M every 3 weeks.
  • Nivolumab
  • Ipilimumab
  • APX005M
Cohort Dose Level 2 (DL2)ExperimentalDL2 will include ipilimumab at 1mg/kg and nivolumab at 3 mg/kg with APX005M of 0.3mg/kg for the induction phase. After 4 cycles we will treat with 360mg of nivolumab and APX005M every 3 weeks.
  • Nivolumab
  • Ipilimumab
  • APX005M

Eligibility Criteria

        Inclusion Criteria:

          -  1. At least 1 site of disease must be accessible to provide repeat biopsies for tumor
             tissue. The biopsy may be waived if not feasible upon discussion with the study PIs.
             This site may be a target lesion as long as it will not be rendered unmeasurable by
             the biopsy procedure.

             2. Age ≥18, able to understand and sign the informed consent form 3. ECOG performance
             status < 2 4. No prior systemic immune therapy for advanced (unresectable) disease.
             Prior targeted therapy is allowed. Adjuvant therapy is allowed provided that at least
             6 months have lapsed from the last dose of an immune checkpoint inhibitor. Prior small
             molecule inhibitors must be discontinued within 2 weeks before starting study.

             5. Life expectancy of at least 6 months 6. A history of previously treated brain
             metastases is allowed, provided that they are stable for at least 4 weeks.

             7. Willingness to undergo tumor biopsy (if amenable) prior to initiation of therapy
             and on trial.

             8. Willingness to provide an archival specimen block, if available, for research 9.
             Normal organ function . 10. Female subjects of childbearing potential should have a
             negative urine or serum pregnancy within 24 hours prior to receiving the first dose of
             study medication. If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required.

             11. Female subjects of childbearing potential should be willing to use a highly
             effective contraception (hormonal or IUD) or be surgically sterile, or abstain from
             heterosexual activity for a period of at least 5 months after the last dose of study
             drug. Subjects of childbearing potential are those who have not been surgically
             sterilized or have not been free from menses for > 1 year.

             12. Male subjects should agree to use an adequate method of contraception starting
             with the first dose of study therapy through at least 7 months after the last dose of
             study drug.

             13. Patients must have at least one measurable lesion at baseline by computed
             tomography (CT) or magnetic resonance imaging (MRI) as per RECIST v1.1 criteria. Tumor
             sites situated in a previously irradiated area, or in an area subjected to other
             loco-reginal therapy, are not considered measurable unless there has been demonstrated
             progression in the lesion.

             14. Prior focal radiotherapy is allowed. Radiation to pulmonary or intestinal sites
             must be completed at least 1 week prior to study Day 1. Radiation to the brain must be
             completed within 4 weeks prior to initiation of treatment. There is no time
             restriction prior to study Day 1 for patients who have received radiation to bone,
             soft tissue or other sites. No radiopharmaceuticals (strontium, samarium) within 8
             weeks before first dose of study drug administration.

             15. Major surgery must be completed at least 2 weeks prior to the first dose of study
             drug administration and patients should have recovered. Wounds must be healed.

        Exclusion Criteria:

          -  1. Untreated brain metastases. 2. A patient who has had prior treatment with immune
             therapy for advanced disease. Prior immune checkpoint inhibitors as adjuvant therapy
             is allowed provided at least 6 months have lapsed from the last dose. Prior targeted
             therapy is allowed as long as 2 weeks have passed.

             3. Use of corticosteroids to control immune related adverse events at enrollment will
             not be allowed, and patients who previously required corticosteroids for symptom
             control must be off steroids for at least 2 weeks. Low-dose steroid use (≤10 mg of
             prednisone or equivalent) as corticosteroid replacement therapy for primary or
             secondary adrenal insufficiency is allowed.

             4. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to prior
             treatments with the exceptions such as alopecia listed in Table 2.

             5. History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver
             toxicity poorly responsive to steroids with prior anti-PD-1/anti-PD-L1 therapy in the
             adjuvant setting.

             6. Presence of leptomeningeal disease. 7. Has active autoimmune disease unrelated to
             use of immune checkpoint inhibitors that has required systemic treatment in the past
             year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

             8. Pregnancy or breast feeding. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she should inform her treating physician
             immediately. Because there is an unknown but potential risk for adverse events in
             nursing infants secondary to treatment of the mother with nivolumab, ipilimumab or
             APX005M, breastfeeding must be discontinued if the mother is enrolled on this trial.

             9. Patients may not be receiving any other investigational agents and may not have
             participated in a study of an investigational agent or using an investigational device
             within 4 weeks of the first dose of treatment.

             10. Either a concurrent condition (including medical illness, such as active infection
             requiring treatment with intravenous antibiotics or the presence of laboratory
             abnormalities) or history of a prior condition that places the patient at unacceptable
             risk if he/she were treated with the study drug or a medical condition that confounds
             the ability to interpret data from the study.

             11. Concurrent, active malignancies in addition to those being studied (other than
             cutaneous squamous cell carcinoma or basal cell carcinoma).

             12. Active (non-infectious) pneumonitis. 13. Has a known Human Immunodeficiency Virus
             (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) acute or chronic infection.

             14. Has received a live vaccine within 30 days prior to the first dose of trial
             treatment.

             15. History of myocardial infarction or unstable angina within 3 months prior to Cycle
             1, Day 1.

             16. Prisoners, or subjects who are under compulsory detention 17. Open wounds and
             active skin infections
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicities
Time Frame:Up to 2 years
Safety Issue:
Description:The safety and tolerability of APX005M in combination with nivolumab and ipilimumab will be assessed by monitoring the of dose-limiting toxicities (DLTs) . This will be defined by both DLTs and any of the following AEs (graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) which occur during the first 9 weeks of ipilimumab + nivolumab + APX005M administration that is not clearly due to a cause other than study medication. DLTs in this study do not include reversible grade 3-4 irAEs, that are acceptable and expected with treatment regimens containing ipilimumab and nivolumab, but do include severe, irreversible, non-endocrine adverse events

Secondary Outcome Measures

Measure:Adverse Events Rate
Time Frame:Up to 2 years
Safety Issue:
Description:The rate of AEs in patients treated with APX005M in combination with nivolumab and ipilimumab will be assessed.
Measure:Adverse Events Pattern
Time Frame:Up to 2 years
Safety Issue:
Description:The pattern of AEs in patients treated with APX005M in combination with nivolumab and ipilimumab will be assessed.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Yale University

Last Updated

July 28, 2020