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

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ClinicalTrials.gov Identifier: NCT04423029
Recruitment Status : Recruiting
First Posted : June 9, 2020
Last Update Posted : October 1, 2020
Sponsor:
Information provided by (Responsible Party):
Dragonfly Therapeutics

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 Intervention/treatment Phase
Solid Tumor Melanoma Renal Cell Carcinoma Urothelial Carcinoma Lung Cancer Head and Neck Squamous Cell Carcinoma Esophageal Cancer Gastric Cancer Ovarian Cancer Prostate Cancer Biological: DF6002 Biological: Nivolumab 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) renal cell carcinoma (RCC).

In Phase 2, DF6002 will be evaluated in combination with nivolumab in the following indication:

Cohort C: Advanced (unresectable or metastatic) urothelial carcinoma.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 260 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 10, 2020
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : December 2024


Arm Intervention/treatment
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 (Renal Cell)
Dose expansion of up to 40 patients with renal cell carcinoma 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 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).
Other Name: Opdivo

Experimental: DF6002 in Combination with Opdivo Expansion (Urothelial)
Dose expansion of up to 40 patients with urothelial carcinoma 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).
Other Name: Opdivo




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



Information from the National Library of Medicine

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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 or ≤Grade 2 alopecia are exceptions)

    Additional Phase 1 Monotherapy and Phase 1b Combination With Nivolumab Expansion Inclusion Criteria:

  7. Has one of the following tumor types: melanoma, non-small cell lung cancer, or triple negative breast cancer
  8. Agrees to undergo a pre-treatment biopsy and another biopsy while on treatment

Inclusion Criteria (General Phase 2)

  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 or ≤Grade 2 alopecia are exceptions.)
  6. Agrees to undergo a pre-treatment biopsy and another biopsy while on treatment.

Additional Inclusion Criteria for Phase 2 (Advanced Melanoma Patients)

  1. Received treatment with an anti PD-1 antibody for at least 6 weeks.
  2. Disease progression was confirmed at least 4 weeks after the initial diagnosis of disease progression while receiving an anti PD-1 antibody.
  3. Received a BRAF inhibitor if the tumor carries a BRAF activating mutation and progressed after the last line of treatment.

Additional Inclusion Criteria for Phase 2 (Advanced Renal Cell Carcinoma)

  1. Any clear cell histology component
  2. Prior treatment with an anti PD-1/PD-L1 antibody or an anti-vascular endothelial growth factor therapy, as monotherapy or in combination.
  3. Received ≤3 prior lines of therapy.

Additional Inclusion Criteria for Phase 2 (Advanced Urothelial Carcinoma)

  1. Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, urinary urothelial, urethra).
  2. Received only one platinum-containing regimen for inoperable locally advanced or metastatic urothelial carcinoma with radiographic progression or with recurrence within 6 months after the last administration of a platinum-containing regimen as an adjuvant, which would be considered failure of a first-line, platinum-containing regimen.
  3. Received no more than 2 lines of therapy (including the platinum-containing regimen) for the treatment of metastatic disease.
  4. Have not received treatment with a check point inhibitor (ie, anti-PD-1 or anti-PD-L1) as a monotherapy or in combination with a platinum-based chemotherapy

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, major surgery, 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. Melanoma patients with brain metastasis(ses) are eligible if they have been stable for 4 weeks after treatment.
  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, or clinically relevant immunodeficiencies.
  10. Known severe hypersensitivity reactions to monoclonal antibodies and any history of anaphylaxis, or uncontrolled asthma
  11. Serious cardiac illness or medical conditions.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04423029


Contacts
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Contact: Sean Rossi (617) 588-0086 ext 760 SeanR@Dragonflytx.com
Contact: Jeannette Hasapidis Jeannette@Dragonflytx.com

Locations
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United States, New York
Montefiore Hospital Recruiting
Bronx, New York, United States, 10461
Contact: Sanjay Goel, MD    718-405-8404    sgoel@montefiore.org   
United States, Rhode Island
Rhode Island Hospital Recruiting
Providence, Rhode Island, United States, 02903
Contact: Andrew Schumacher    401-444-3234    ASchumacher@Lifespan.org   
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37205
Contact: Referral Office    615-329-7478    DDUreferrals@sarahcannon.com   
Sponsors and Collaborators
Dragonfly Therapeutics
Investigators
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Study Director: Tapan Maniar, MD Dragonfly Therapeutics
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Responsible Party: Dragonfly Therapeutics
ClinicalTrials.gov Identifier: NCT04423029    
Other Study ID Numbers: DF6002-001
First Posted: June 9, 2020    Key Record Dates
Last Update Posted: October 1, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dragonfly Therapeutics:
Immunotherapy
Cytokine
Solid Tumor
Melanoma
Renal Cell Carcinoma
Urothelial Carcinoma
IL-12
DF6002
Additional relevant MeSH terms:
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Carcinoma
Melanoma
Carcinoma, Renal Cell
Carcinoma, Transitional Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Carcinoma, Squamous Cell
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Kidney Diseases
Urologic Diseases
Head and Neck Neoplasms
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents