APX005M With Nivolumab and Cabiralizumab in Advanced Melanoma, Non-small Cell Lung Cancer or Renal Cell Carcinoma

A Phase I/Ib Study of APX005M in Combination With Nivolumab and Cabiralizumab in Patients With Advanced Melanoma, Non-small Cell Lung Cancer or Renal Cell Carcinoma Whose Disease Has Progressed on Anti-PD- 1/PD-L1 Therapy

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.

Study Overview

• Status: Completed
• Conditions: Renal Cell Carcinoma; Non-small Cell Lung Cancer; Advanced Melanoma
• Intervention / Treatment: Drug: APX005M; Drug: Cabiralizumab; Drug: Nivolumab

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 Advanced Solid Tumors; Cabiralizumab 4mg/kg plus APX005M 0.03 mg/kg administered in 14 day cycles.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.
Experimental: Cohort 2 Advanced Solid Tumors; Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.03 mg/kg administered in 14 day cycles.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.; Drug: Nivolumab; Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.
Experimental: Cohort 3 Advanced Solid Tumors; Cabiralizumab 4mg/kg plus APX005M 0.1 mg/kg administered in 14 day cycles.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.
Experimental: Cohort 4 Advanced Solid Tumors; Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.1 mg/kg administered in 14 day cycles.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.; Drug: Nivolumab; Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.
Experimental: Cohort 5 Advanced Solid Tumors; Cabiralizumab 4mg/kg plus APX005M 0.3 mg/kg administered in 14 day cycles.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.
Experimental: Cohort 6 Advanced Solid Tumors; Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.3 mg/kg administered in 14 day cycles.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.; Drug: Nivolumab; Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.
Experimental: Cohort 7 Advanced Melanoma; Patients will be treated at the estimated APX005M RP2D in combination with nivolumab 240 mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.; Drug: Nivolumab; Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.
Experimental: Cohort 8 NSCLC; Patients will be treated at the estimated APX005M RP2D in combination with nivolumab 240 mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.
Experimental: Cohort 9 RCC; Patients will be treated at the estimated APX005M RP2D in combination with nivolumab 240 mg IV and cabiralizumab 4 mg/kg on day 1 of each 14-day cycle.	Drug: APX005M; APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.; Drug: Cabiralizumab; Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.; Drug: Nivolumab; Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability Measured by Assessing Serious Adverse Events (SAEs)and Adverse Events (AEs)	AEs and SAEs will be examined with (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03.	From study enrollment up to 12 months.
Safety and Tolerability Measured by Eastern Cooperative Oncology Group(ECOG) Performance Status	This 5-point scale ranges from full functioning (0) to dead (5)	From study enrollment up to 12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Measured by Objective Response Rate (ORR)	ORR will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria v. 1.1. The RECIST categories used for the target lesion are complete response (CR), partial response (PR), stable disease (NR/SD), and progressive disease (PD).	Six months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK) of APX005M Assessed by Area Under the Curve (AUC).	This outcome will be assessed by blood collection.	12 weeks
Pharmacokinetics (PK) of APX005M Assessed by Minimum Blood Plasma Concentration (Cmin).	This outcome will be assessed by blood collection.	12 weeks
Pharmacokinetics (PK) of APX005M Assessed by Clearance (CL).	This outcome will be assessed by blood collection.	12 weeks
Pharmacokinetics (PK) of APX005M Assessed by Volume of Distribution (Vss)	This outcome will be assessed by blood collection.	12 weeks
Pharmacokinetics (PK) of APX005M Assessed by Peak Plasma Concentration (Cmax).	This outcome will be assessed by blood collection.	12 weeks
Tissue-based Pharmacodynamics (PD) of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by CD8+ T Cells .	This outcome will be assessed with tissue biopsies.	Change from baseline to 8 weeks.
Tissue-based Pharmacodynamics (PD) of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by CD163+ Macrophages .	This outcome will be assessed with tissue biopsies.	Change from baseline to 8 weeks.
Blood-based Pharmacodynamics (PD) of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by Circulating CD163+ Macrophages .	This outcome will be assessed via blood collection.	Change from baseline to 8 weeks.
Blood-based Pharmacodynamics (PD) of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by Circulating CD8+ T Cells.	This outcome will be assessed via blood collection.	Change from baseline to 8 weeks.
Cytokine-based Pharmacodynamic (PD) Biomarkers of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by CD40L Levels.	This outcome will be assessed via blood collection.	Change from baseline to 8 weeks.
Cytokine-based Pharmacodynamic (PD) Biomarkers of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by IL-10 Levels.	This outcome will be assessed via blood collection.	Change from baseline to 8 weeks.
Cytokine-based Pharmacodynamic (PD) Biomarkers of APX005M, in Combination With Nivolumab and Cabiralizumab Assessed by Interferon-gamma Levels .	This outcome will be assessed via blood collection.	Change from baseline to 8 weeks.
Efficacy Measured by Progression-free Survival (PFS)	PFS will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria v. 1.1.	From study enrollment up to 6 years.
Efficacy Measured by Overall Survival (OS)	OS will be ascertained by review of the National Death Index, medical records and follow-up phone calls.	From study enrollment up to 6 years.

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI); Apexigen America, Inc.
• Investigators: Principal Investigator: Harriet Kluger, MD, Yale University

Publications and helpful links

General Publications

• Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, Ralabate A, Johnson B, Levit NS, Anderson G, Zelterman D, Wei W, Mahajan A, Trifan O, Bosenberg M, Kaech SM, Perry CJ, Damsky W, Gettinger S, Sznol M, Hurwitz M, Kluger HM. A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non-Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1. Clin Cancer Res. 2021 Sep 1;27(17):4757-4767. doi: 10.1158/1078-0432.CCR-21-0903. Epub 2021 Jun 17.

Study record dates

Study Major Dates

• Study Start (Actual): June 9, 2018
• Primary Completion (Actual): January 5, 2022
• Study Completion (Actual): May 15, 2024

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: April 10, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: June 21, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Kidney Neoplasms; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma; Melanoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 2000021757; 5P50CA121974-15 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No