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).
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).
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
