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

NCT03502330 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 20000217575P50CA121974-15
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Advanced Melanoma; Non-small Cell Lung Cancer; Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Efficacy Measured by Objective Response Rate (ORR)

  Six months.

Other Outcomes (14)

• Pharmacokinetics (PK) of APX005M Assessed by Area Under the Curve (AUC).

  12 weeks

• Pharmacokinetics (PK) of APX005M Assessed by Minimum Blood Plasma Concentration (Cmin).

  12 weeks

• Pharmacokinetics (PK) of APX005M Assessed by Clearance (CL).

  12 weeks

Study Arms (9)

Cohort 1 Advanced Solid Tumors

EXPERIMENTAL

Cabiralizumab 4mg/kg plus APX005M 0.03 mg/kg administered in 14 day cycles.

Drug: APX005M; Drug: Cabiralizumab

Cohort 2 Advanced Solid Tumors

EXPERIMENTAL

Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.03 mg/kg administered in 14 day cycles.

Drug: APX005M; Drug: Cabiralizumab; Drug: Nivolumab

Cohort 3 Advanced Solid Tumors

EXPERIMENTAL

Cabiralizumab 4mg/kg plus APX005M 0.1 mg/kg administered in 14 day cycles.

Drug: APX005M; Drug: Cabiralizumab

Cohort 4 Advanced Solid Tumors

EXPERIMENTAL

Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.1 mg/kg administered in 14 day cycles.

Drug: APX005M; Drug: Cabiralizumab; Drug: Nivolumab

Cohort 5 Advanced Solid Tumors

EXPERIMENTAL

Cabiralizumab 4mg/kg plus APX005M 0.3 mg/kg administered in 14 day cycles.

Drug: APX005M; Drug: Cabiralizumab

Cohort 6 Advanced Solid Tumors

EXPERIMENTAL

Nivolumab 240 mg plus Cabiralizumab 4mg/kg plus APX005M 0.3 mg/kg administered in 14 day cycles.

Drug: APX005M; Drug: Cabiralizumab; Drug: Nivolumab

Cohort 7 Advanced Melanoma

EXPERIMENTAL

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; Drug: Cabiralizumab; Drug: Nivolumab

Cohort 8 NSCLC

EXPERIMENTAL

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; Drug: Cabiralizumab

Cohort 9 RCC

EXPERIMENTAL

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; Drug: Cabiralizumab; Drug: Nivolumab

Interventions

APX005M DRUG

APX005M is a humanized Immunoglobulin G (IgG) 1 agonistic monoclonal antibody that binds cluster of differentiation (CD) 40. APX005M is administered by intravenous infusion.

Cohort 1 Advanced Solid Tumors; Cohort 2 Advanced Solid Tumors; Cohort 3 Advanced Solid Tumors; Cohort 4 Advanced Solid Tumors; Cohort 5 Advanced Solid Tumors; Cohort 6 Advanced Solid Tumors; Cohort 7 Advanced Melanoma; Cohort 8 NSCLC; Cohort 9 RCC

Cabiralizumab DRUG

Cabiralizumab is a humanized Immunoglobulin G (IgG) 4 monoclonal antibody directed against Colony stimulating factor 1 receptor (CSF1R). Cabiralizumab is administered by intravenous infusion.

Cohort 1 Advanced Solid Tumors; Cohort 2 Advanced Solid Tumors; Cohort 3 Advanced Solid Tumors; Cohort 4 Advanced Solid Tumors; Cohort 5 Advanced Solid Tumors; Cohort 6 Advanced Solid Tumors; Cohort 7 Advanced Melanoma; Cohort 8 NSCLC; Cohort 9 RCC

Nivolumab DRUG

Nivolumab is a humanized IgG4 monoclonal antibody directed against programmed cell death 1 (PD-1). Nivolumab is administered by intravenous infusion.

Cohort 2 Advanced Solid Tumors; Cohort 4 Advanced Solid Tumors; Cohort 6 Advanced Solid Tumors; Cohort 7 Advanced Melanoma; Cohort 9 RCC

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.
• 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.
• Age ≥18, able to understand and sign the informed consent form.
• ECOG performance status \< 2.
• 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.
• Life expectancy of at least 6 months.
• A history of previously treated brain metastases is allowed, provided that they are stable for at least 4 weeks.
• Willingness to undergo mandatory tumor biopsy prior to initiation of therapy and before the fifth cycle.
• Willingness to provide an archival specimen block, if available, for research.
• Patients must have normal organ and marrow function (as outlined in Section 3.2.2).
• 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.

You may not qualify if:

• Untreated brain metastases.
• 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.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has had prior treatment with any other CSF1R inhibitor or CD40 agonist
• 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.
• 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.
• 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.
• Presence of leptomeningeal disease.
• 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.
• 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.
• 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.
• 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.
• Concurrent, active malignancies in addition to those being studied.
• Active (non-infectious) pneumonitis.
• Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV), or Hepatitis C (HCV) acute or chronic infection.

Sponsors & Collaborators

• Yale University: lead
• Bristol-Myers Squibb: collaborator
• Apexigen America, Inc.: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Yale Cancer Center

New Haven, Connecticut, 06510, United States

Location

Related Publications (2)

• Djureinovic D, Weiss SA, Krykbaeva I, Qu R, Vathiotis I, Moutafi M, Zhang L, Perdigoto AL, Wei W, Anderson G, Damsky W, Hurwitz M, Johnson B, Schoenfeld D, Mahajan A, Hsu F, Miller-Jensen K, Kluger Y, Sznol M, Kaech SM, Bosenberg M, Jilaveanu LB, Kluger HM. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better. Mol Cancer. 2023 Nov 14;22(1):182. doi: 10.1186/s12943-023-01884-x.

  PMID: 37964379 DERIVED

• 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.

  PMID: 34140403 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell

Interventions

sotigalimab; cabiralizumab; Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Harriet Kluger, MD
• Organization: Harvey and Kate Cushing Professor of Medicine (Oncology) and of Dermatology; Director, Yale SPORE in Skin Cancer, Yale Cancer Center

harriet.kluger@yale.edu

(203) 200-6622

Study Officials

• Harriet Kluger, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: April 18, 2018
• Study Start: June 9, 2018
• Primary Completion: January 5, 2022
• Study Completion: May 15, 2024
• Last Updated: July 3, 2024
• Results First Posted: August 18, 2023

Record last verified: 2024-06

Locations

US (1)