| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer, advanced solid tumors |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
• To characterize the safety, tolerability, dose limiting toxicities (DLTs), maximum tolerated dose (MTD)/maximum administered dose (MAD) and recommended phase 2 dose (RP2D) and schedule for future study of DRP-104 as monotherapy for the IV and subQ administration route and to determine the recommended phase 2 route of administration (RP2R)
• To further characterize the safety and tolerability of the RP2D
• To characterize the safety, tolerability, DLTs, MTD/MAD of the RP2R of DRP-104 in combination with atezolizumab in patients with advanced solid tumors (excluding primary CNS tumors and HCC)
• To further characterize the safety and tolerability of the RP2D of the RP2R of DRP-104 in combination with atezolizumab in the same patient population enrolled in Part 3
Phase 2a
• To characterize the safety and tolerability of DRP-104 as monotherapy using the RP2R
• To assess the objective response rate of DRP-104 as monotherapy by RECIST1.1 in patients with NSCLC or SCCHN |
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| E.2.2 | Secondary objectives of the trial |
Phase 1 single agent:
• To characterize the pharmacokinetics (PK) of DRP-104 and its metabolites, M1 and DON, as monotherapy administered IV and subQ
• To evaluate the preliminary antitumor activity (ORR) of DRP-104 as monotherapy by RECISTv1.1 in patients with advanced solid tumors (excluding primary CNS tumors and HCC) or PCWG 3.0 criteria
• To evaluate disease control rate (DCR), duration of response (DOR), time to response (TTR), progression-free survival (PFS) and overall survival (OS)
Phase 1 DRP-104 + atezolizumab
• To characterize the PK of atezolizumab and DRP-104 and its metabolites, M1 and DON
• To evaluate the ORR of DRP-104 in combination with atezolizumab by RECIST 1.1 and iRECIST in patients with advanced solid tumors or PCWG criteria
• To evaluate DCR, DOR, TTR, PFS and OS
Phase 2a:
• To characterize the PK of DRP-104 and its metabolites, as monotherapy
• To evaluate DCR, DOR, TTR, PFS and OS of DRP-104 monotherapy in patient with NSCLC or SCCHN |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Signed Informed Consent Form.
• Male or female, 18 years of age or older.
• Target Population - all patients regardless of study part:
o Diagnosis of advanced or recurrent, histologically or cytologically confirmed, solid malignancy that is either metastatic or unresectable.
o Patients must have measurable disease per RECIST 1.1 (Eisenhauer et al., 2009; Schwartz et al., 2016) with the exception of castration-resistant prostate cancer (CRPC) who should have progression based on the PCWG 3.0 criteria (Scher et al., 2016). Lesions in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
o At time of enrollment, patients must have progressed on, be intolerant of, decline, or be ineligible for, all available standard of care therapies with proven benefit.
Part 2 – dose escalation/phase 2a:
Cohort 2: locally advanced or metastatic NSCLC with the presence of a known mutation in KEAP1, NFE2L2 and/or STK11.
- The mutational status of KEAP1, NFE2L2, STK11 and KRAS genes will be performed by locally validated DNA tests. Testing will be performed by sequencing DNA extracted from tissue samples and/or from DNA extracted from blood samples using methods of targeting circulating tumor DNA (ctDNA).
- Patients with known EGFR mutations, BRAF V600E mutations, ALK rearrangements, ROS1 rearrangements, NTRK gene fusions, RET gene fusion and MET exon 14 skipping mutations are excluded; other known mutations identified by a locally validated DNA tests are allowed.
- Patients must have received at least a platinum doublet chemotherapy and an anti-PD-(L)1 antibody unless patients declined or are ineligible for treatment.
- Received no more than 3 lines of systemic anticancer therapy in the recurrent or metastatic setting. Patients with a known KRAS G12C mutation should receive an available, locally approved treatment, which will be considered as one of the 3 prior lines of systemic anticancer therapy, unless patients declined, are intolerant of or are ineligible for treatment.
Cohort 3: Recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck (SCCHN) (the oropharynx, oral cavity, hypopharynx or larynx).
- Patient must have received platinum containing chemotherapy and an anti-PD-(L)1 antibody in the recurrent or metastatic setting, unless patients declined or are ineligible for treatment
- Received no more than 3 lines of systemic anticancer therapy in the recurrent or metastatic setting
Part 3 and 4 – DRP-104 + Atezolizumab dose escalation/expansion
- Must have prior exposure to therapy with any agent specifically targeting checkpoint pathway inhibition (such as anti-PD-1, anti-PD-L1 and/or anti-CTLA-4 antibody)
- Received no more than 3 lines of systemic anticancer therapy in the recurrent or metastatic setting
• Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1.
• Patient must consent to allow the acquisition of existing FFPE tumor tissue, as 17 unstained slides, for performance of correlative studies.
• All SCCHN patients, all NSCLC patients and patients being treated with the combination of DRP-104 and atezolizumab will be required to undergo pre-treatment and post-treatment core or excisional biopsies. These patients will still require an archival tumor sample.
• Adequate baseline organ function as defined in the protocol.
• Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must agree to use one highly effective method of contraception, as detailed in the protocol.
• Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a total of 14 weeks post completion of DRP-104 and 8 months after the final dose of atezolizumab.
• Women must not be pregnant or breastfeeding or have intention of becoming pregnant during the study treatment or for a total of 5 weeks after completion of DRP-104 and 5 months after the final dose of atezolizumab.
For details on the inclusion criteria, please, refer to the protocol. |
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| E.4 | Principal exclusion criteria |
• Target disease exceptions
o Patients with primary central nervous system tumors and hepatocellular carcinoma.
o Patients with progressive or symptomatic brain metastases. Patients with brain metastases may be included in this trial as long as the brain metastases have completed definitive treatment at least 14 days prior to meeting eligibility and are radiologically stable (i.e., without evidence of progression on screening imaging assessment, [Note: repeat imaging should be performed during study screening]). Patients must be clinically stable and have discontinued anti-seizure medications and steroids, except for physiologic steroid dosing (≤10 mg/day of prednisone equivalents), for at least 14 days prior to Cycle 1 Day 1.
o Leptomeningeal disease.
o Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 8 weeks prior to Cycle 1 Day 1 and must have discontinued steroids, except for physiologic steroid dosing (≤10 mg/day of prednisone equivalents).
o Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
- Patients with indwelling catheters (e.g., PleurX) are allowed regardless of drainage frequency.
• Prior therapy
o Patients who have not recovered to grade 1 or baseline from adverse events (CTCAE v 5.0) related to prior therapy excluding alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ grade 3. Note: any lymphopenia due to previous therapy must have recovered to grade 1 or baseline prior to enrollment.
o Prior glutaminase inhibitor use (excluded in Part 2: Cohorts 2 and 3 only)
o Prior systemic anticancer treatment (i.e. chemotherapy, biologic therapy [i.e. small molecular inhibitors], monoclonal antibodies, investigational agents]) within 21 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1. If a patient is receiving an anti-PD-1 or anti-PD-L1 antibody on a shorter frequency, ie every two weeks, then the patient is eligible if last dose is 14 days prior to Cycle 1 Day 1. Note: Patients must have recovered from all AEs due to previous therapies to CTCAE v 5.0 grade 1 or baseline, excluding lymphopenia, alopecia, peripheral neuropathy and ototoxicity, which are excluded if >= grade 3.
o Prior small port palliative radiotherapy within 14 days prior to Cycle 1 Day 1 or within 42 days prior to Cycle 1 Day 1 from definitive local control radiation (any dose greater than 50 Gy, within 42 days of Cycle 1 Day1). Patients must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
o Anti-androgen therapies for prostate cancer, such as bicalutamide, within 4 weeks prior to enrollment. Second-line hormone therapies such as enzalutamide, abiraterone, or orteronel within 2 weeks prior to Cycle 1 Day 1. Patients with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Patients with prostate cancer may also remain on low-dose prednisone or prednisolone up to 10 mg/day.
- Patients with hormone positive breast cancer may remain on endocrine therapy.
o Prior therapy with long acting myeloid growth factor or from a short acting myeloid growth factor within 14 days or 7 days prior to Cycle 1 Day 1, respectively
o Any major surgery within 21 days prior to Cycle 1 Day 1 or who have not recovered from side effects of such procedure (CTCAE v 5.0 grade 1 or baseline)
o Patients receiving potent inducers of CYP 3A4/5 (including St. John’s Wort) that cannot be discontinued at least 14 days prior to Cycle 1 Day 1
• Medical history and concurrent disease
o Malignant disease, other than that being treated in this study. Note: Participants with 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 are not excluded. Other exceptions include malignancies that were treated curatively and have not recurred within 3 years prior to study treatment and any malignancy considered indolent and has never required therapy.
o Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority
o Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required.
Please, refer to protocol for further exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1 dose escalation and expansion (Parts 1 - Cohort 1a/1b, 2 –Cohort 1a/1b advanced solid tumor only, 3, and 4):
• Frequency of DLTs at each dose level associated with DRP-104 as monotherapy and in combination with atezolizumab in a 21 day cycle
• Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
• The RP2D of DRP-104 will be decided based on a synthesis of safety, tolerability, PK, PD and preliminary efficacy data from the IV and subQ dose escalation
Phase 2a (Part 2 – Cohort 2 NSCLC and Cohort 3 SCCHN):
• Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
• ORR defined as the proportion of patients with a best overall confirmed response of complete response (CR) or partial response (PR) as assessed per RECIST 1.1 by investigator assessment |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| as defined in endpoint and according to assessment schedule |
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| E.5.2 | Secondary end point(s) |
Phase 1 single agent dose escalation and expansion (Parts 1-Cohort 1a/1b and 2 – Cohort 1a/1b advanced solid tumor cohort only):
• PK parameters such as but not limited to Cmax, Tmax, AUC, T1/2 and Cmin for DRP-104 and its metabolites (M1, DON).
• ORR defined as the proportion of patients with a best overall confirmed response (BOR) of complete response (CR) or partial response (PR) as assessed per RECIST 1.1 or PCWG 3.0 criteria by investigator assessment
• Disease control rate (DCR) defined as the proportion of patients with a BOR of CR or PR or SD.
• Duration of response (DOR), defined as time from date of first documented objective response (CR or PR) to the first documented progression or death due to any cause
• Time to response (TTR), calculated as time from first dose of study drug to first documented objective response (CR or PR)
• Progression-free survival (PFS) defined as time from first dose of study drug to progression or death due to any cause
• Overall survival (OS), defined as time from first dose of study drug to death due to any cause
Phase 1 DRP-104 + atezolizumab escalation and expansion (Parts 3 and 4)
• PK parameters such as but not limited to Cmax, Tmax, AUC, T1/2 and Cmin for DRP-104 and its metabolites (M1, DON). Trough concentrations of atezolizumab will be assessed.
• ORR, defined as the proportion of patients with a BOR of complete response(CR) or partial response (PR) as assessed per RECIST 1.1 or PCWG 3.0 (prostate cancer patients) and iRECIST criteria by investigator assessment
• DCR, DOR, TTR, PFS ad OS
Phase 2a (Part 2 – Cohort 2 NSCLC and Cohort 3 SCCHN cohorts)
• PK parameters such as but not limited to Cmax, Tmax, AUC, T1/2 and Cmin for DRP-104 and its metabolites (M1, DON)
• DCR, DOR, TTR, PFS and OS
• If needed to advance to next steps of development, efficacy parameters will be assessed by independent central review of imaging scans |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| as defined in endpoint and according to assessment schedule |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability and preliminary antitumor activity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Monotherapy and in combination with atezolizumab (different dose of test drug DRP-104) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Monotherapy and in combination with atezolizumab (different dose of test drug DRP-104) |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Taiwan |
| Korea, Republic of |
| United States |
| Germany |
| Spain |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study will be when all patients have completed at least 12 cycles or 9 months of treatment, whichever is earlier, or discontinued study earlier per criteria defined in Protocol section 8.1.3 Discontinuation of study drug/ treatment. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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