A First-in-Human Phase 1/2 Trial to Determine the Safety and the Pharmacokinetic Profile of DSP-0509, a Synthetic Toll-Like Receptor 7 (TLR-7) Agonist, Administered as Monotherapy and in Combination With Pembrolizumab in Adult Patients With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- DSP-0509
- Conditions
- Neoplasms
- Sponsor
- Sumitomo Pharma America, Inc.
- Enrollment
- 36
- Locations
- 5
- Primary Endpoint
- Determination of the Recommended Phase 2 Dose (RP2D) by Assessing Dose-limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
This is a multi-center, Phase 1 / 2 clinical study for patients with advanced solid tumors. The study consists of 2 treatment arms - a monotherapy arm and a combination arm. The monotherapy arm has 1 part: Dose Escalation (Part A). The combination arm has Dose Escalation (Part B) only.
Detailed Description
The primary objective of Monotherapy Arm A is to determine the MTD or RP2D of DSP-0509 when administered as a single agent. Approximately 21 to 30 patients with advanced solid tumors will be enrolled. Several provisional dose levels of DSP-0509, with approximately 3 to 6 patients at each level may be tested in patients with advanced solid tumors. DSP-0509 will be administered as a single agent q2w beginning on Day 1. The primary objective of Combination Therapy Arm B is to determine the RP2D of DSP-0509 when administered in combination with pembrolizumab, using a BLRM approach. The combination arm will enroll approximately 21 to 30 patients with advanced solid tumors that are (a) metastatic or unresectable and recurrent, and/or refractory to available therapy, (b) a condition for which pembrolizumab is an approved treatment, and (c) in patients who have shown either primary or acquired resistance to an ICI. DSP-0509 will be administered on Day 1 and then every 2 weeks thereafter. Pembrolizumab will be initiated on Day 1. The primary objective of Combination Therapy Arm C is to determine preliminary efficacy in the form of the ORR of DSP-0509 when administered in combination with pembrolizumab to an expansion cohort of patients with HNSCC, using a Bayesian Adaptive design approach. Combination Arm C will enroll approximately 20 to 40 patients with HNSCC tumors that are (a) metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in patients who have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, and (c) who have subsequently shown either primary or acquired resistance to ICIs. Dose escalation of DSP-0509 in combination with 400 mg pembrolizumab q6w will start at the same dose of DSP-0509 as the highest (not exceeding the MTD) level tested in the combination regimen with 200 mg pembrolizumab q3w. Upon completion of the DLT evaluation period for the first DSP-0509 dose level tested in combination with 400 mg pembrolizumab q6w in newly enrolled patients, if this dose level is found not to exceed the MTD, any ongoing patients receiving DSP-0509 in combination with pembrolizumab 200 mg q3w will be allowed, at the investigator's discretion, to transition to the 400 mg pembrolizumab q6w regimen, while maintaining the originally assigned DSP-0509 dose level.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must fulfill each of the following requirements:
- •Must have a histologically or cytologically confirmed advanced solid tumor that meets the following additional specifications
- •Monotherapy Part A (Dose Escalation) advanced solid tumor that is metastatic or unresectable and recurrent and /or refractory to available therapy.
- •Combination Part B (Dose Escalation)- advanced solid tumors that are (a) metastatic or unresectable and recurrent and/or refractory to available therapy; (b) a condition for which pembrolizumab is an approved treatment: and (c) in patients who either have shown primary or acquired resistance to immune checkpoint inhibitors (ICIs)
- •Combination Arm C (Dose Expansion), Phase 2 - Advanced HNSCC tumors of the oropharynx, oral cavity, hypopharynx, larynx, lip, or sinus that are (a) metastatic or unresectable, and recurrent and/or refractory to available therapy, (b) in patients who have been treated with pembrolizumab or other PD-1 or PD-L1 inhibitors in monotherapy, and (c) who have subsequently shown primary or acquired resistance to ICIs.
- •For enrollment in both arms:
- •Must be ≥ 18 years of age
- •Should have all side effects of any prior therapy or procedures for any medical condition recovered to CTCAE ≤ Grade 1 (except alopecia).
- •Must have at least 1 measurable lesion by computed tomography or magnetic resonance imaging per RECIST v1.
- •Must have a life expectancy ≥ 3 to 6 months.
Exclusion Criteria
- •Patients with any of the following will be excluded from the study:
- •For enrollment in both arms:
- •Has received prior therapy with a TLR agonist, excluding a topical TLR agonist.
- •Has received anticancer chemotherapy (including molecular-targeted drugs), radiotherapy, immunotherapy (eg, vaccines or cytokines), or investigational agents within the 3 weeks before the first dose of DSP-
- •Local palliative radiotherapy is permitted
- •Receives concurrent systemic (oral or IV) steroid therapy \> 10 mg prednisone daily or its equivalent for an underlying condition.
- •Not fully recovered from major surgery before the first dose of DSP-
- •Has central nervous system (CNS) metastases (including leptomeningeal metastases, spinal metastases) or CNS primary tumors, eg, glioblastoma.
- •Has a history of seizures other than isolated febrile seizure in childhood; has a history of a cerebrovascular accident or transient ischemic attack less than 6 months ago.
- •Has effusions (pleural, pericardial, or ascites) requiring drainage.
Arms & Interventions
Monotherapy Arm - Part A
Dose Escalation Drug DSP-0509
Intervention: DSP-0509
Combination arm - Part B
Dose Escalation Drug DSP-0509, Pembrolizumab
Intervention: DSP-0509, Pembrolizumab
Combination arm - Part C
Dose Expansion, Drug DSP-0509, Pembrolizumab
Intervention: DSP-0509, Pembrolizumab
Outcomes
Primary Outcomes
Determination of the Recommended Phase 2 Dose (RP2D) by Assessing Dose-limiting Toxicities (DLTs)
Time Frame: 28 days
Determination of the MTD of DSP-0509 When Given in Combination With Pembrolizumab by Assessing Dose-limiting Toxicities (DLTs).
Time Frame: 28 days
MTD of DSP-0509 in patients enrolled into the Combination Arm during the dose escalation part of the study.
Determination of RP2D of DSP-0509 When Given in Combination With Pembrolizumab by Assessing DLTs
Time Frame: 28 days
Data to be derived from patients enrolled into the Combination Arm - Part B (Phase 1).
Preliminary Antitumor Activity of DSP-0509 in Combination With Pembrolizumab in Patients With Head & Neck Squamous Cell Carcinoma (HNSCC) Who Have Shown Primary or Acquired Resistance to Immune Checkpoint Inhibitors (ICIs)
Time Frame: 4 weeks
Data to be derived from patients enrolled into the Combination Arm - Part C (Phase 2)
Number of Participants With Dose-limiting Toxicities (DLTs) Within the First 6 Weeks of Dosing
Time Frame: From the time of first dose to 6 weeks after the first dose
Secondary Outcomes
- Evaluate Single Agent DSP-0509-induced Changes in Cytokine Levels.(8 weeks)
- Evaluate Change in Cytokine Levels Induced by DSP-0509 in Combination With Pembrolizumab.(8 weeks)
- DoR by iRECIST(6 months)
- Duration of Response (DoR) by RECIST(6 months)
- ORR by Immune RECIST (iRECIST)(From date of first dose to 6 months post first dose)
- PFS by iRECIST(12 months)
- Evaluate Pharmacokinetics (PK) for Single Agent DSP-0509 by Assessing Plasma Concentration.(8 weeks)
- Objective Response Rate (ORR) by RECIST(From date of first dose to 6 months post first dose)
- Progression Free Survival (PFS) by RECIST(12 months)
- Evaluate Pharmacokinetics (PK) for Combo Agents DSP-0509 and Pembrolizumab by Assessing Plasma Concentration.(8 weeks)