A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study to Investigate the Safety, Tolerability, PK, PD, and Efficacy of SRK-181 Alone and in Combination With Anti-PD-(L)1 Antibody Therapy in Patients With Locally Advanced or Metastatic Solid Tumors (DRAGON)
Overview
- Phase
- Phase 1
- Intervention
- SRK-181
- Conditions
- Cancer
- Sponsor
- Scholar Rock, Inc.
- Enrollment
- 112
- Locations
- 22
- Primary Endpoint
- Safety and tolerability of single agent SRK-181
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This was a multi-center, open-label, Phase 1, first-in-human (FIH), dose-escalation, and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of SRK-181 administered alone and in combination with anti-PD-(L)1 therapy in adult patients with locally advanced or metastatic solid tumors. The study was divided into 3 treatment parts (Part A1, Part A2, and Part B) and a Long-Term Extension Phase (LTEP).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patient has a histologically documented solid tumor that is metastatic or locally advanced, for which SoC therapy does not exist, has failed in the patient, or is not tolerated by the patient, or for which the patient has been assessed by the Investigator as not being a suitable candidate or otherwise ineligible for the SoC therapy.
- •For Part A2:
- •o Patient must have a history of anti-PD-(L)1 antibody nonresponse presenting (based upon the Investigator's assessment) either as progressive disease or stable disease (e.g., not improving, but also not worsening, clinically or radiographically) after at least 3 cycles of treatment with the most recent anti-PD-(L)1 antibody therapy (alone or in combination with chemotherapy) approved for that tumor type. (Note: if the duration of prior anti-PD-1 therapy is shorter than 3 cycles and the reason for discontinuation is progressive disease, the progression should be associated with clinical deterioration.)
- •For Part B Cohort NSCLC, UC, MEL and ccRCC:
- •Patient must be diagnosed with one of the following disease-specific solid tumors of NSCLC, UC, or MEL, and must have a history of primary nonresponse to anti-PD-1 therapy (alone or in combination with other therapy), presenting the best response (based upon the Investigator's assessment) either as progressive disease or stable disease (e.g., not improving, but also not worsening, clinically or radiographically) after at least 3 cycles of treatment.
- •For Cohort NSCLC, patients who have genomic tumor aberrations for which a targeted therapy is available (e.g., anaplastic lymphoma kinase, EGFR) must have progressed on an approved therapy for these aberrations or did not tolerate an approved therapy for these aberrations, or were not considered suitable candidates/ were otherwise ineligible for an approved therapy for these aberrations.
- •For Cohort ccRCC, patients must have a histologically confirmed diagnosis of RCC with a predominant clear cell component and must have received at least 1 prior line of anti-PD-1 treatment (alone or in combination with other therapy) and have had disease progression clinically or radiographically on the most recent anti-PD-1 treatment
- •Up to 3 lines of treatment are allowed between the last dose of anti-PD-1 and enrollment.
- •For Part B Cohort HNSCC:
- •Patients must have a histologically confirmed diagnosis of recurrent or metastatic HNSCC that is non-amendable to curative therapy (e.g., radiation or surgery).
Exclusion Criteria
- •For Part A1 only:
- •Patient has had anti-PD-(L)1 antibody therapy ≤ 28 days prior to the first dose of SRK-
- •Patient is receiving concurrent anti-cancer treatment, including anti-PD-(L)1 antibody therapy, either approved or investigational, within 28 days prior to the first dose of SRK-
- •For Part A2 and Part B only:
- •Patient is receiving concurrent anti-cancer treatment, with the exception of an anti-PD-(L)1 antibody therapy for Part A2 or Part B, either approved or investigational, within 28 days prior to the first dose of SRK-
- •Patient has received biologic therapy (except for anti-PD-(L)1 antibody therapy for Part A2 or Part B), \<28 days prior to the first dose of SRK-
- •Patient has received systemic cytotoxic chemotherapy (except for in combination with anti-PD-(L)1 antibody therapy) \<28 days prior to the first dose of SRK-
- •Patient has received targeted small molecule therapy within 5 half-lives of the compound prior to the first dose of SRK-
- •Patient has a history of intolerance or treatment discontinuation due to severe irAE or other adverse reaction from prior anti-PD-(L)1 antibody therapy.
- •Patient has a hypersensitivity to anti-PD-(L)1 antibody therapy.
Arms & Interventions
Part A1: Dose Escalation
Part A1 determined the maximum tolerated dose (MTD) or maximum administered dose (MAD) of SRK-181 as a single agent and the recommended Phase 2 dose (RP2D) of SRK-181 as a single-agent.
Intervention: SRK-181
Part A2: Dose Escalation
Part A2 determined the MTD or MAD of SRK-181 in combination with anti-PD-(L)1 antibody therapy and the RP2D of SRK-181 in combination with anti-PD-(L)1 antibody therapy for use in Part B.
Intervention: SRK-181
Part A2: Dose Escalation
Part A2 determined the MTD or MAD of SRK-181 in combination with anti-PD-(L)1 antibody therapy and the RP2D of SRK-181 in combination with anti-PD-(L)1 antibody therapy for use in Part B.
Intervention: anti-PD-(L)1 antibody therapy
Part B: Dose Expansion
In Part B, parallel cohorts of patients with Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma (UC), Cutaneous Melanoma (MEL), Clear Cell Renal Cell Carcinoma (ccRCC), Head and Neck Squamous Cell Carcinoma (HNSCC), or other advanced or metastatic solid tumor type that is not NSCLC, UC, MEL, or ccRCC were enrolled to confirm the tolerability of the RP2D of SRK-181 (determined in Part A2) and to evaluate the anti-tumor activity of SRK-181 in combination with an anti-PD-(L)1 antibody therapy.
Intervention: SRK-181
Part B: Dose Expansion
In Part B, parallel cohorts of patients with Non-Small Cell Lung Cancer (NSCLC), Urothelial Carcinoma (UC), Cutaneous Melanoma (MEL), Clear Cell Renal Cell Carcinoma (ccRCC), Head and Neck Squamous Cell Carcinoma (HNSCC), or other advanced or metastatic solid tumor type that is not NSCLC, UC, MEL, or ccRCC were enrolled to confirm the tolerability of the RP2D of SRK-181 (determined in Part A2) and to evaluate the anti-tumor activity of SRK-181 in combination with an anti-PD-(L)1 antibody therapy.
Intervention: anti-PD-(L)1 antibody therapy
Long Term Extension Phase (LTEP)
Patients may continue treatment in a LTEP: * Part A1: Patients may continue treatment with SRK-181 as a single agent at the RP2D in the LTEP following 3 cycles of treatment with SRK-181 as a single agent in Part A1. * Part A2: Patients may continue treatment with SRK-181 at the RP2D in combination with anti-PD-(L)1 antibody therapy in the LTEP following 3 cycles of treatment with SRK-181 in combination with anti-PD-(L)1 antibody therapy in Part A2. * Part B: Patients may continue treatment with SRK-181 in combination with anti-PD-(L)1 antibody therapy following 9 cycles of treatment with SRK-181 in combination with anti-PD-(L)1 antibody therapy in Part B
Intervention: SRK-181
Long Term Extension Phase (LTEP)
Patients may continue treatment in a LTEP: * Part A1: Patients may continue treatment with SRK-181 as a single agent at the RP2D in the LTEP following 3 cycles of treatment with SRK-181 as a single agent in Part A1. * Part A2: Patients may continue treatment with SRK-181 at the RP2D in combination with anti-PD-(L)1 antibody therapy in the LTEP following 3 cycles of treatment with SRK-181 in combination with anti-PD-(L)1 antibody therapy in Part A2. * Part B: Patients may continue treatment with SRK-181 in combination with anti-PD-(L)1 antibody therapy following 9 cycles of treatment with SRK-181 in combination with anti-PD-(L)1 antibody therapy in Part B
Intervention: anti-PD-(L)1 antibody therapy
Outcomes
Primary Outcomes
Safety and tolerability of single agent SRK-181
Time Frame: The first 21 days of study treatment
Dose limiting toxicities (DLTs), as assessed by the Investigator, but not including toxicities clearly related to disease progression or intercurrent illness
Safety and tolerability of SRK-181 in combination with anti-PD-(L)1 antibody therapy
Time Frame: The first 21 days of study treatment
Dose limiting toxicities (DLTs), as assessed by the Investigator, but not including toxicities clearly related to disease progression or intercurrent illness
Secondary Outcomes
- PK of SRK-181 alone and in combination with anti-PD-(L)1 antibody therapy(Cycle 1 and Cycle 3 (each cycle is 21 days))
- Anti-tumor activity of SRK-181, alone or in combination wit anti-PD-(L)1 antibody therapy as potential indicators of clinical response(6 months)