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Dose Escalation of DF6002 in Patients With Advanced Solid Tumors, and Expansion in Selected Indications

  • Clinicaltrials.gov identifier

    NCT04423029

  • Recruitment Status

    Recruiting

  • First Posted

    June 9, 2020

  • Last update posted

    July 26, 2021

Study Description

Brief summary:

This study is a Phase 1/2, open-label, dose-escalation study with a consecutive parallel-group efficacy expansion study, designed to determine the safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumor activity of DF6002 as monotherapy and in combination with nivolumab.

  • Condition or Disease:Endometrial Cancer
    Triple Negative Breast Cancer
    Prostate Cancer
    Ovarian Cancer
    Gastric Cancer
    Esophageal Cancer
    Lung Cancer
    Head and Neck Squamous Cell Carcinoma
    Urothelial Carcinoma
    Renal Cell Carcinoma
    Melanoma
    Solid Tumor
  • Intervention/Treatment: Biological: DF6002
    Biological: Nivolumab
  • Phase: Phase 1/Phase 2

Detailed Description

This study is a Phase 1/2, open-label, dose-escalation study with a consecutive parallel-group efficacy expansion study, designed to determine the safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumor activity of DF6002 as monotherapy and in combination with nivolumab. The study consists of 3 parts: Phase 1: Dose-escalation as a monotherapy using a 3+3 design, with Phase 1 Cohort Expansion. Phase 1b: Dose-escalation as a combination with nivolumab using a 3+3 design, with Phase 1b Cohort Expansion. Phase 2: Efficacy Expansion using a group sequential design. In Phase 2, DF6002 will be evaluated as a monotherapy in the following indications: Cohort 2A: Advanced (unresectable or metastatic) melanoma. Cohort 2B: Advanced (unresectable or metastatic) non-small cell lung cancer (NSCLC). In Phase 2, DF6002 will be evaluated in combination with nivolumab in the following indication: Cohort 2C: Advanced (unresectable or metastatic) melanoma. Cohort 2D: Advanced (unresectable or metastatic) NSCLC. In each study phase, patients will receive DF6002 on Day 1 every 4 weeks (Q4W). Patients will receive DF6002 until confirmed progressive disease (PD), unacceptable toxicity (ie, dose-limiting toxicity [DLT]), or any reason for withdrawal from the study or Investigational Medicinal Product (IMP) occurs.

Study Design

  • Study Type: Interventional
  • Estimated Enrollment: 380 participants
  • Allocation: Non-Randomized
  • Intervention Model: Sequential Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase 1/2, First-In-Human, Multi-Part, Open-Label, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of DF6002 as a Monotherapy and in Combination With Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumors, and Expansion in Selected Indications
  • Actual Study Start Date: July 2020
  • Estimated Primary Completion Date: September 2022
  • Estimated Study Completion Date: December 2024

Arms and interventions

Arm Intervention/treatment
Experimental: DF6002 In Combination with Opdivo Escalation
3+3 dose escalation of subcutaneous DF6002 in combination with intravenous Opdivo.
Biological: DF6002
DF6002 is a monovalent human interleukin-12 (IL12)-constant fragment (Fc) fusion protein that binds to the IL12 receptor.

Biological: Nivolumab
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody, which binds to the programmed death-1 receptor (PD-1).
Experimental: DF6002 Monotherapy Dose Escalation
3+3 dose escalation of subcutaneous DF6002 as monotherapy in patients with solid tumors.
Biological: DF6002
DF6002 is a monovalent human interleukin-12 (IL12)-constant fragment (Fc) fusion protein that binds to the IL12 receptor.
Experimental: DF6002 Monotherapy Expansion (Melanoma)
Dose expansion of up to 40 patients with melanoma receiving subcutaneous DF6002 as monotherapy.
Biological: DF6002
DF6002 is a monovalent human interleukin-12 (IL12)-constant fragment (Fc) fusion protein that binds to the IL12 receptor.
Experimental: DF6002 Monotherapy Expansion (NSCLC)
Dose expansion of up to 40 patients with non-small cell lung cancer receiving subcutaneous DF6002 as monotherapy.
Biological: DF6002
DF6002 is a monovalent human interleukin-12 (IL12)-constant fragment (Fc) fusion protein that binds to the IL12 receptor.
Experimental: DF6002 in Combination with Opdivo Expansion (Melanoma)
Dose expansion of up to 40 patients with melanoma receiving subcutaneous DF6002 in combination with intravenous Opdivo.
Biological: DF6002
DF6002 is a monovalent human interleukin-12 (IL12)-constant fragment (Fc) fusion protein that binds to the IL12 receptor.

Biological: Nivolumab
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody, which binds to the programmed death-1 receptor (PD-1).
Experimental: DF6002 in Combination with Opdivo Expansion (NSCLC)
Dose expansion of up to 40 patients with non-small cell lung cancer receiving subcutaneous DF6002 in combination with intravenous Opdivo.
Biological: DF6002
DF6002 is a monovalent human interleukin-12 (IL12)-constant fragment (Fc) fusion protein that binds to the IL12 receptor.

Biological: Nivolumab
Nivolumab is a human immunoglobulin G4 (IgG4) monoclonal antibody, which binds to the programmed death-1 receptor (PD-1).

Outcome Measures

  • Primary Outcome Measures: 1. Assessment of the number of dose limiting toxicities experienced on study with monotherapy DF6002 as defined per criteria in the study protocol [ Time Frame: First 3 weeks on treatment for each subject. ]
    To assess the number of adverse events experienced during treatment with monotherapy DF6002 that meet dose limiting toxicity criteria per the study protocol.
  • 2. Assessment of the number of dose limiting toxicities experienced on study with combination therapy of DF6002 and nivolumab as defined per criteria in the study protocol [ Time Frame: First 3 weeks on treatment for each subject in the combination therapy cohort. ]
    To assess the number of adverse events experienced during treatment with combination therapy of DF6002 and nivolumab that meet dose limiting toxicity criteria per the study protocol.
  • 3. Assess overall response rate [ Time Frame: Through 90 days after completion of the study, an average of 1 year. ]
    To assess the Overall Response Rate (ORR) per RECIST version 1.1 criteria of patients in the Phase 2 expansion cohorts.
  • Secondary Outcome Measures: 1. Assess number of treatment emergent adverse events throughout study [ Time Frame: Until 30 days after the last treatment of the last subject enrolled in the Phase 2 portion of the study. ]
    Characterize the safety profile of DF6002 by assessing the number of adverse events occurring while on treatment with DF6002.
  • 2. Determine serum concentrations of DF6002 at various timepoints [ Time Frame: From start of treatment up through 28 days after last treatment ]
    Concentration vs time of DF6002 will be measured using blood samples taken a various time points on study
  • 3. Assess Duration of Response [ Time Frame: From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months ]
    To assess duration of response using RECIST 1.1 criteria
  • 4. Assess Best Overall Response [ Time Frame: Through 90 days after completion of the study, an average of 1 year ]
    To assess best overall response using RECIST 1.1 criteria
  • 5. Assess Overall Survival [ Time Frame: Time from enrollment in the study until death, measured up to 2 years after last treatment on study ]
    To assess overall survival following treatment
  • 6. Assess Overall Response Rate [ Time Frame: Time from enrollment in the study until up to 2 years after last treatment on study ]
    To assess overall response rate according to Investigator judgment

Eligibility Criteria

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

Criteria

Inclusion Criteria (General Phase 1 and Phase 1b): 1. Male or female patients aged ≥ 18 years 2. Histologically or cytologically proven locally advanced or metastatic solid tumors, for which no standard therapy exists or standard therapy has failed among the following tumor types: melanoma, non-small cell lung cancer, small cell lung cancer, head and neck squamous cell, urothelial, gastric, esophageal, cervical, hepatocellular, merkel cell, cutaneous squamous cell carcinoma, renal cell, endometrial, triple-negative breast, ovarian, and prostate. 3. ECOG performance status of 0 or 1 4. Clinical or radiological evidence of disease 5. Adequate hematological, hepatic and renal function 6. Resolution of toxic effect(s) of prior anti-cancer therapy to ≤Grade 1 (Patients with ≤Grade 2 neuropathy, ≤Grade 2 endocrinopathy or ≤Grade 2 alopecia are exceptions) 7. Effective contraception for women of child-bearing potential as defined by World Health Organization guidelines for 1 "highly effective" method or 2 "effective" methods Additional Phase 1 Monotherapy and Phase 1b Combination With Nivolumab Expansion Inclusion Criteria: 1. Has one of the following tumor types: melanoma, non-small cell lung cancer, or triple negative breast cancer 2. Agrees to undergo a pre-treatment biopsy and another biopsy while on treatment Expansion Inclusion Criteria specific to Melanoma: 1. Histologically confirmed, unresectable Stage III or Stage IV melanoma, as specified in the American Joint Committee on Cancer staging system. 2. Participants with ocular or uveal melanoma are ineligible. 3. PD-L1 status must be documented if available. 4. BRAF (V600) mutation status must be known. Both BRAF-mutated and wild type participants are permitted in this cohort. 5. BRAF-mutated participants must have been treated with approved targeted therapies. 6. Must have documented progressive or recurrent disease on or after discontinuation of anti-PD-(L)1 therapy (administered as monotherapy or as part of a combination) as per RECIST 1.1 criteria: 7. Participants who received anti-PD-(L)1 in the adjuvant setting must have documented progressive or recurrent disease on or within 6 months of discontinuation of anti-PD-(L)1 therapy (administered as monotherapy or as part of a combination) as per RECIST 1.1 criteria. Expansion Inclusion Criteria specific to NSCLC: 1. Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV, or recurrent disease. 2. Participants must have recurrent or progressive disease during or after platinum doublet-based chemotherapy or at least two prior lines of systemic therapy for advanced or metastatic disease OR Must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease. 3. Participants must have received and progressed on or after anti-PD-(L)1 therapy, if available. 4. Status for actionable mutations (e.g., EGFR, ALK, ROS1, RET, etc.) must be known (when testing is available as per country/region standard of care practices); participants with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for, standard tyrosine kinase inhibitors (as available per country/region standard of care practices). Expansion Inclusion Criteria specific to TNBC: 1. Histologically confirmed unresectable, locally advanced or metastatic triple negative breast cancer.PD-L1 status, HER2-negative, estrogen receptor-negative, and progesterone receptor-negative status must be evaluated by local institutions before enrolment per guidelines of the American Society of Clinical Oncology and the College of American Pathologists. 2. Patients must not have received an anti PD-1/PD-L1 for the treatment of the metastatic disease, but the administration of an anti PD-1/PD-L1 in the adjuvant setting is acceptable. 3. Patients must have received one line of chemotherapy for the treatment of their metastatic disease, and experience progression during or after that line of chemotherapy. 4. Patients must have not received more than one line of chemotherapy for the treatment of their unresectable, recurrent or metastatic disease. Inclusion Criteria for Phase 2 (General) 1. Male or female patients aged ≥ 18 years. 2. ECOG performance status of 0 or 1 3. Clinical or radiological evidence of measurable disease. 4. Adequate hematological, hepatic and renal function. 5. Resolution of toxic effect(s) of prior anti-cancer therapy to ≤Grade 1. (Patients with ≤Grade 2 neuropathy, ≤Grade 2 endocrinopathy or ≤Grade 2 alopecia are exceptions.) 6. Participants must have received and progressed on or after anti-PD-(L)1 therapy. 7. Effective contraception for women of child-bearing potential as defined by World Health Organization guidelines for 1 "highly effective" method or 2 "effective" methods Additional Inclusion Criteria for Phase 2 (Advanced Melanoma Patients) 1. Participants who received anti-PD-(L)1 in the advanced/metastatic setting, must have documented progressive or recurrent disease on or within 3 months of discontinuation of anti-PD-(L)1 therapy 2. Participants who received anti-PD-(L)1 in the adjuvant setting must have documented progressive or recurrent disease on or within 6 months of discontinuation of anti-PD-(L)1 therapy 3. Disease progression was confirmed at least 4 weeks after the initial diagnosis of disease progression while receiving an anti PD-1 antibody. 4. BRAF mutation status must be known and treated with approved targeted therapies. 5. Received a BRAF inhibitor if the tumor carries a BRAF activating mutation and progressed after the last line of treatment. 6. Participants with ocular or uveal melanoma are ineligible. 7. Confirmation of radiographic progression on prior anti-PD-(L)1 therapy is required with a scan confirming progression at least 4 weeks after the initial progression Additional Inclusion Criteria for Phase 2 (Non-small Cell Lung Cancer) 1. Participants must have recurrent or progressive disease during or after platinum doublet-based chemotherapy or at least two prior lines of systemic therapy for advanced or metastatic disease OR must have recurrent or progressive disease within 6 months after completing platinum-based chemotherapy for local disease. 2. Status for actionable mutations must be known; participants with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for, standard tyrosine kinase inhibitors Exclusion Criteria for All Patients (All Phases) 1. Prior treatment with rhIL2 or any recombinant long acting drug containing an IL2 moiety. 2. Concurrent anticancer treatment (with the exception of palliative bone directed radiotherapy), immune therapy, or cytokine therapy (except for erythropoietin), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days before the start of study treatment. 3. Previous malignant disease other than the current target malignancy within the last 3 years, with the exception of basal or squamous cell carcinoma of the skin, localized prostate cancer or cervical carcinoma in situ. 4. Rapidly progressive disease. 5. Any Grade 2 and higher neurological or pulmonary toxicity during a treatment with an anti-PD-1 or PD-L1 agent administered as a monotherapy. 6. Active or history of central nervous system (CNS) metastases unless all of the following criteria are met: 1. CNS lesions are asymptomatic and previously treated. 2. Patient does not require ongoing steroid treatment daily for replacement for adrenal insufficiency. 3. Imaging demonstrates stability of disease 28 days from last treatment for CNS metastases. 7. Receipt of any organ transplantation, autologous or allogeneic stem-cell transplantation. 8. Significant acute or chronic infections, or active or latent hepatitis B or active hepatitis C. 9. Preexisting autoimmune disease needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years, clinically relevant immunodeficiencies, or fever within 7 days of Day 1. 10. Known severe hypersensitivity reactions to monoclonal antibodies and any history of anaphylaxis, or uncontrolled asthma 11. Serious cardiac illness or medical conditions. 12. History of life-threatening toxicity related to prior immune therapy except those that are unlikely to re-occur with standard countermeasures.

Contacts and Locations

Contacts

Contact: Sean Rossi (617) 588-0086 ext 7060 Sean.rossi@Dragonflytx.com

Contact: Jeannette Hasapidis Jeannette.hasapidis@Dragonflytx.com

Locations

United States, California
University of California Irvine
Orange

United States, Florida
University of Miami
Miami

United States, Massachusetts
Dana-Farber Cancer Institute
Boston

United States, Michigan
Henry Ford Hospital
Detroit

United States, Minnesota
Regions Hospital - Cancer Care Center
Saint Paul

United States, New York
Montefiore Hospital
Bronx

United States, New York
Roswell Park Comprehensive Cancer Center
Buffalo

United States, Ohio
University Hospitals Cleveland Medical Center
Cleveland

United States, Rhode Island
Rhode Island Hospital
Providence

United States, Tennessee
Sarah Cannon Research Institute
Nashville

United States, Texas
The University of Texas MD Anderson Cancer Center
Houston

United States, Utah
Huntsman Cancer Institute and Hospital
Salt Lake City

United States, Virginia
Virginia Cancer Specialists
Fairfax

Sponsors and Collaborators

Dragonfly Therapeutics

Bristol-Myers Squibb

Investigators

Study Director: Tapan Maniar, MD Dragonfly Therapeutics

More Information

  • Responsible Party: Dragonfly Therapeutics
  • ClinicalTrials.gov Identifier: NCT04423029 History of Changes
  • Other Study ID Numbers: DF6002-001
  • First Posted: June 9, 2020 Key Record Dates
  • Last Update Posted: July 26, 2021
  • Last Verified: July 2021
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by Dragonfly Therapeutics: DF6002
    IL-12
    Urothelial Carcinoma
    Renal Cell Carcinoma
    Melanoma
    Solid Tumor
    Cytokine
    Immunotherapy
  • Additional relevant MeSH terms: Squamous Cell Carcinoma of Head and Neck
    Carcinoma, Transitional Cell
    Triple Negative Breast Neoplasms
    Endometrial Neoplasms
    Carcinoma, Renal Cell
    Melanoma
    Carcinoma