APX005M With Nivolumab and Cabiralizumab in Advanced Melanoma, Non-small Cell Lung Cancer or Renal Cell Carcinoma
Condition: Advanced Melanoma; Non-small Cell Lung Cancer; Renal Cell Carcinoma
MeSH terms: Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Melanoma; Carcinoma, Renal Cell
Intervention: APX005M; Cabiralizumab; Nivolumab
Intervention description: APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.; Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.
Intervention MeSH terms: Nivolumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This trial is a phase 1/1b study to evaluate the safety, efficacy, and tolerability of
      APX005M in combination with nivolumab and cabiralizumab.

      The phase 1 dose escalation portion of the study will enroll patients with advanced solid
      tumors melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) in 6
      cohorts to determine the recommended phase II dose (RP2D) of APX005M.

      The phase 1b dose expansion portion will study the triple drug combination separately in the
      three disease cohorts: melanoma, NSCLC, and RCC.
    

Eligibility criteria:

        Inclusion Criteria:

        Must have one of the following diagnoses:

        Melanoma: Unresectable stage III or stage IV melanoma, irrespective of BRAF status, with
        histologic or cytologic confirmation.

        RCC: Histologic or cytologically documented, locally advanced unresectable or metastatic
        RCC irrespective of histologic subtype

        NSCLC: Histologic or cytologically documented, locally advanced or metastatic (i.e. Stage
        IIIB not eligible for definitive chemoradiotherapy, stage IV, or recurrent) NSCLC. Patients
        known to harbor an ALK rearrangement or EGFR mutation known to be sensitive to FDA-approved
        tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression
        (during or after treatment) or intolerance to an FDA approved ALK TKI or EGFR TKI,
        respectively. Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR
        T790M tumor must have received prior osimertinib. Patients with crizotinib-treated ALK
        rearranged NSCLC must have received a next generation ALK inhibitor.

        Additional Inclusion Criteria:

          1. Biopsy proven metastatic melanoma, NSCLC or RCC whose disease has progressed on a
             prior regimen containing a PD-1 or PD-L1 inhibitor, without intervening therapy.

          2. At least 1 site of disease must be accessible to provide repeat biopsies for tumor
             tissue. This site may be a target lesion as long as it will not be made unmeasurable
             by the biopsy procedure.

          3. Age ≥18, able to understand and sign the informed consent form.

          4. ECOG performance status < 2.

          5. Any number of previous treatments. Other prior systemic therapies must have been
             administered at least 4 weeks before administration of the study drugs; the exception
             to this is small molecule inhibitors, which must be stopped at least 2 weeks or after
             five half-lives of the drug, whichever is shorter, prior to the start of the study
             drugs.

          6. Life expectancy of at least 6 months.

          7. A history of previously treated brain metastases is allowed, provided that they are
             stable for at least 4 weeks.

          8. Willingness to undergo mandatory tumor biopsy prior to initiation of therapy and
             before the fifth cycle.

          9. Willingness to provide an archival specimen block, if available, for research.

         10. Patients must have normal organ and marrow function (as outlined in Section 3.2.2).

         11. Female subject 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.

         12. 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.

         13. 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.

         14. 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.

             a. Tumor sites situated in a previously irradiated area, or in an area subjected to
             other loco-regional therapy, are not considered measurable unless there has been
             demonstrated progression in the lesion. Sites for biopsy must be distinct from target
             lesions used for efficacy assessment.

         15. Prior focal radiotherapy is allowed. Radiation to brain, pulmonary or intestinal sites
             must be completed at least 4 weeks prior to study Day 1. 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.

         16. Prior surgery that requires general anesthesia must be completed at least 1 week
             before first dose of study drug administration. Surgery requiring local/epidural
             anesthesia must be completed at least 72 hours before first dose of study drug
             administration and patients should have recovered.

        Exclusion Criteria:

          1. Untreated brain metastases.

          2. A patient who has had prior immune therapy or chemotherapy, within 4 weeks prior to
             study Day 1, or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse
             events due to a previously administered agent will be excluded. The exception is
             targeted therapy that must have been completed at least 2 weeks or after 5 half-lives,
             which ever is shorter, prior to study Day 1. Patients who have had prior ipilimumab
             must have received their last dose no less than 4 weeks prior to study Day 1.

               1. Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

               2. Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the
                  inclusion requirements for laboratory parameters.

          3. Has had prior treatment with any other CSF1R inhibitor or CD40 agonist

          4. 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.

          5. Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to prior
             treatments with the exception of clinically insignificant adverse events such as
             alopecia, clinically insignificant laboratory abnormalities, clinically insignificant
             rash and Grade 2 neuropathy.

          6. History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver toxicity
             poorly responsive to steroids with prior anti-PD-1/anti-PDL1 monotherapy.

          7. Presence of leptomeningeal disease.

          8. 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.

          9. 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, cabiralizumab or
             APX005M, breastfeeding must be discontinued if the mother is enrolled on this trial.

         10. 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.

         11. 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.

         12. Concurrent, active malignancies in addition to those being studied.

         13. Active (non-infectious) pneumonitis.

         14. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C
             (HCV) acute or chronic infection.

         15. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

         16. History of myocardial infarction or unstable angina within 3 months prior to Cycle 1,
             Day 1.

         17. Prisoners, or subjects who are under compulsory detention

         18. Current or history of clinically significant muscle disorders (e.g., myositis), recent
             unresolved muscle injury, or any condition known to elevate serum CK levels

         19. History of anti-drug antibodies, severe allergic, anaphylactic, or other
             infusion-related reaction to a previous biologic agent

         20. Concomitant use of statins while on study. However, a patient using statins for over 3
             months prior to study drug administration and in stable status without CK rise may be
             permitted to enroll

         21. Open wounds and active skin infections

         22. Uveal melanoma in the Phase Ib dose expansion trial