First-in-human Study of DRP-104 (Sirpiglenastat) as Single Agent and in Combination With Atezolizumab in Patients With Advanced Solid Tumors.

• ClinicalTrials.gov Identifier: NCT04471415
• Recruitment Status: Recruiting
• First Posted: July 15, 2020
• Last Update Posted: April 13, 2021
• Sponsor: Dracen Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Dracen Pharmaceuticals, Inc.

Study Description

Brief Summary:

The purpose of this study is to characterize the safety, tolerability, pharmacokinetics, pharmaco-dynamics and preliminary anti-tumor activity of DRP-104 (sirpiglenastat) administered via intravenous infusion or via subcutaneous injection as a single agent and in combination with atezolizumab in patients with advanced solid tumors and to assess preliminary safety and efficacy of which route of administration (intravenous or subcutaneous) will be selected for further development for the other two expansions of patients, advanced non-small cell lung cancer (NSCLC) with defined genetic mutations, and advanced squamous cell carcinoma of the head and neck (SCCHN).

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumor; Non-Small Cell Lung Cancer Recurrent; Squamous Cell Carcinoma of Head and Neck; Non Small Cell Lung Cancer Metastatic	Drug: DRP-104; Biological: atezolizumab	Phase 1; Phase 2

Detailed Description:

This study will be conducted in 4 Parts:

Part 1: Phase 1 single-agent dose escalation of DRP-104 (sirpiglenastat) in patients with advanced solid tumors to define the MTD (up to approximately 50 patients for each intravenous and subcutaneous cohort)

Part 2, Once the MTD of DRP-104 for the IV and subQ route of administration will be determined in Part 1, Part 2 will include 2 specific cohorts: Cohort 2 and 3 with one only selected formulation. Once the MTD of DRP-104 has been declared for either the IV or suQ cohort, Cohort 1 of Part 2 will separately expand for each cohort. -Cohort 1: Phase 1 single-agent safety expansion at the of DRP-104 in patients with advanced solid tumors (N= minimum of 14 and up to 20 patients for each intravenous and subcutaneous cohorts); The Sponsor will determine at completion of Phase 1 which route of administration will be further developed and continued for all subsequent Cohorts 2 and 3 and Parts 3 and Part 4 in combination with atezolizumab.

• Cohort 2: Phase 2a expansion at the of DRP-104 in patients with locally advanced or metastatic NSCLC whose tumors contain a KEAP1 mutation, NFE2L2 mutation and/or STK11 mutation (N=55 patients)
• Cohort 3: Phase 2a expansion at the MTD of DRP-104 in recurrent, unresectable or metastatic SCCHN (N=15-25 patients).

Part 3: Phase 1 combination dose escalation of DRP-104 (sirpiglenastat) (with either IV or subcutaneous formulation selected) and atezolizumab in patients with advanced solid tumors previously treated with an anti-PD-1, anti PD-L1, and/or anti-CTLA-4 antibody, starting one dose level below the MTD of single-agent DRP-104 and in combination with atezolizumab (up to approximately N=12 patients).

Part 4: Phase 1 combination safety expansion at the MTD of DRP-104 (with either IV or subcutaneous formulation selected)with atezolizumab in a similar patient population as the dose-escalation (N=14 patients).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 246 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose Escalation cohort, followed by Dose Expansion cohort, followed by NSCLC, SCCHN and combination with atezolizumab cohorts.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 and Phase 2a, First-in-human Study of DRP-104 (Sirpiglenastat), a Glutamine Antagonist, in Adult Patients With Advanced Solid Tumors
• Actual Study Start Date: August 31, 2020
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1a & Part 1b; Single-agent dose escalation of DRP-104 to define the MTD (up to approximately 50 patients) starting at Dose Level 1 of 3.3 mg/m2 via intravenous injection Single-agent dose escalation of DRP-104 to define the MTD (up to approximately 50 patients) starting at Dose Level 1 at 10 mg via subcutaneous injection	Drug: DRP-104; DRP-104 administered intravenously over 1 hour, three times per week (TIW) (Monday, Wednesday, Friday) for 2 consecutive weeks, one week off DRP-104 administered subcutaneously twice weekly (Monday/Thursday or Tuesday/Friday) every week
Experimental: Part 2; Cohort 1a: Phase 1 single-agent safety expansion at the of intravenous DRP-104 in patients with advanced solid tumors (N=14 up to 20 patients);; Cohort 1b: Phase 1 single-agent safety expansion at the of subcutaneous DRP-104 in patients with advanced solid tumors (N=14 up to 20 patients);; Cohort 2: Phase 2a expansion at the of DRP-104 at the recommended selected route of administration (intravenous or subcutaneous) in patients with locally advanced or metastatic NSCLC whose tumors contain a KEAP1 mutation, NFE2L2 mutation and/or STK11 mutation (N=55 patients); Cohort 3: Phase 2a expansion at the MTD of DRP-104 at the recommended selected route of administration (intravenous or subcutaneous) in recurrent, unresectable or metastatic SCCHN (N=15-25 patients).	Drug: DRP-104; DRP-104 administered intravenously over 1 hour, three times per week (TIW) (Monday, Wednesday, Friday) for 2 consecutive weeks, one week off DRP-104 administered subcutaneously twice weekly (Monday/Thursday or Tuesday/Friday) every week
Experimental: Part 3; Dose escalation of DRP-104 at 1 dose level below declared MTD at the selected recommended route of administration (intravenous or subcutaneous) in combination with atezolizumab in patients with advanced solid tumors previously treated with an anti-PD-1, anti PD-L1, and/or anti-CTLA-4 antibody (up to approximately (N=12 patients).	Drug: DRP-104; DRP-104 administered intravenously over 1 hour, three times per week (TIW) (Monday, Wednesday, Friday) for 2 consecutive weeks, one week off DRP-104 administered subcutaneously twice weekly (Monday/Thursday or Tuesday/Friday) every week; Biological: atezolizumab; atezolizumab administered intravenously over 1 hour at 1200 mg once every 3 weeks.
Experimental: Part 4; Dose expansion at the MTD of DRP-104 at the selected recommended route of administration (intravenous or subcutaneous) with atezolizumab (N=14 patients).	Drug: DRP-104; DRP-104 administered intravenously over 1 hour, three times per week (TIW) (Monday, Wednesday, Friday) for 2 consecutive weeks, one week off DRP-104 administered subcutaneously twice weekly (Monday/Thursday or Tuesday/Friday) every week; Biological: atezolizumab; atezolizumab administered intravenously over 1 hour at 1200 mg once every 3 weeks.

Outcome Measures

Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD [ Time Frame: anticipated 1 year ]
   Safety
2. Area under the plasma concentration versus time curve (AUC) [ Time Frame: anticipated 1 year ]
3. Cmax of DRP-104 [ Time Frame: anticipated 1 year ]

Secondary Outcome Measures :

1. Overall Response Rate [ Time Frame: anticipated 2 year ]
2. Disease control rate [ Time Frame: anticipated 2 year ]
3. Duration of response [ Time Frame: anticipated 2 year ]
4. Progression-free survival [ Time Frame: anticipated 2 year ]
5. Overall survival (OS) [ Time Frame: anticipated 2 year ]

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:

• Diagnosis of advanced or recurrent, histologically or cytologically confirmed, measurable by RECIST 1.1 metastatic or unresectable solid tumor
• Patient must have progressed on, be intolerant of, decline, or be ineligible for, all available standard of care therapies
• Part 2: locally advanced or metastatic NSCLC with KEAP1, NFE2L2 and/or STK11 mutation ; Patients must have received at least a platinum doublet chemotherapy and an anti-PD-(L)1 antibody; Received up to 3 lines of systemic anticancer therapy in the recurrent or metastatic setting
• Part 2: Recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck (SCCHN) (oropharynx, oral cavity, hypopharynx or larynx); Patient must have received platinum containing chemotherapy and antiPD-(L)1 antibody in recurrent or metastatic setting
• Part 3 and 4 - DRP-104 + atezolizumab Prior exposure to any checkpoint inhibitor (anti-PD-1, anti-PD-L1, anti-PDL2, and/or anti-CTLA-4 antibody)
• ECOG performance 0 or 1
• Patient must consent to allow acquisition of existing FFPE tumor tissue; If unavailable, patient must consent to new pre-treatment tumor biopsy
• All SCCHN patient, all NSCLC patients and all patients treated with combination of DRP-104 and atezolizumab will be required to undergo pre-treatment and post-treatment core or excisional biopsies.
• Pre-treatment and post-treatment core or excisional biopsies are optional for all remaining patients
• Adequate baseline organ function as defined by: Absolute neutrophil count ≥ 1.5 × 109/L (1500/µL); Hemoglobin ≥ 9 g/dL ;Platelets ≥ 75 × 109/L (75,000/µL); Hepatic Total bilirubin ≤1.5 × upper limit of normal (ULN): PT/INR and PTT ≤1.5 × ULN, unless treated with warfarin; AST(SGOT)/ALT(SGPT) ≤3 × ULN or ≤ 5 × ULN for patients with liver metastases; Creatinine clearance ≥ 60 ml/min/1.73m2 measured or calculated
• Cardiac QTc (Fridericia) <470 ms
• Women of child-bearing potential and men who are sexually active must agree to use one highly effective method of contraception

Exclusion Criteria:

• Patients with primary central nervous system tumors and hepatocellular carcinoma
• Patients with progressive or symptomatic brain metastases
• Leptomeningeal disease
• Spinal cord compression not definitively treated with surgery and/or radiation
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage
• Prior glutaminase inhibitor use
• Prior systemic anticancer treatment (i.e. chemotherapy, biologic therapy, monoclonal antibodies, investigational agents) within 21 days or 5 half-lives, whichever is shorter
• Anti-androgen therapies for prostate cancer, such as bicalutamide, within 4 weeks prior to enrollment
• Prior small port palliative radiotherapy within 14 days of start of Cycle 1
• Any major surgery within 21 days from start of Cycle 1
• Secondary malignancy that is progressing or has required active treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
• Has a known history of HIV, or HBV
• Gastrointestinal (GI) function impairment or GI disease
• Significant, uncontrolled heart disease and/or cardiac repolarization abnormality
• Exclusion specific to only Part 3 and 4 (DRP-104 combined with atezolizumab): History of severe allergic, anaphylactic to chimeric or humanized antibodies or fusion proteins; Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells; Prior anti-PD-1, anti-PD-L1 and/or anti CTLA4- agent, patient must not have had a serious (> Grade 3) immune-related AE requiring treatment; History of autoimmune disease except hypothyroidism on thyroid replacement hormone therapy; History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis; Patients with underlying condition requiring systemic corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications or other systemic immunosuppressant medications may be enrolled in the study after approval by the Medical Monitor; Evidence or history of active or latent tuberculosis infection; Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1

Contacts and Locations

Contacts

Contact: Margaret Dugan, MD; 973-489-7163; mdugan@dracenpharma.com

Contact: Francois Lafleur, MPH; 917-330-3971; FLafleur@dracenpharma.com

Locations

United States, Arizona

HonorHealth; Recruiting

Scottsdale, Arizona, United States, 85258

Principal Investigator: Sunil Sharma, MD

United States, California

UCLA; Recruiting

Los Angeles, California, United States, 90095

Principal Investigator: Aaron Lisberg, MD

United States, Maryland

Johns Hopkins Kimmel Institute; Recruiting

Baltimore, Maryland, United States, 21231

Principal Investigator: Tanguy Siewert, MD

United States, New York

NYU Langone; Not yet recruiting

New York, New York, United States, 10016

Principal Investigator: Vamsidhar Velcheti, MD

Mount Sinai Health Systems; Recruiting

New York, New York, United States, 10029-6574

Principal Investigator: Deborah Doroshow, MD

United States, North Carolina

University of North Carolina; Not yet recruiting

Chapel Hill, North Carolina, United States, 27514

Principal Investigator: Shetal Patel, MD

United States, Tennessee

Sarah Cannon Research Institute; Recruiting

Nashville, Tennessee, United States, 37203

Principal Investigator: Melissa Johnson, MD

Vanderbilt University Medical Center; Recruiting

Nashville, Tennessee, United States, 37232

Principal Investigator: Michael Gibson, MD

Germany

Centrum fur Integrieerte Onkologie; Not yet recruiting

Cologne, Germany, 50924

Contact: MD

Principal Investigator: Matthias Scheffler, MD

Sub-Investigator: Jurgen Wolfe, MD

Sponsors and Collaborators

Dracen Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Sunil Sharma, MD; HonorHealth Director

More Information

Additional Information:

Company website with scientific background on DRP-104 

• Responsible Party: Dracen Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04471415
• Other Study ID Numbers: DRA-104-001; 2020-002770-27 ( EudraCT Number )
• First Posted: July 15, 2020
• Last Update Posted: April 13, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Squamous Cell Carcinoma of Head and Neck; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Head and Neck Neoplasms; Atezolizumab; Antineoplastic Agents