Clinical Trial 21080

• Overview

  Study Title:

  A Phase 1, Open-Label, Dose-Escalation, and Dose-Expansion Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of SRK-181 Administered Alone or in Combination with a Checkpoint Inhibitor in Patients with Locally Advanced or Metastatic Solid Tumors (DRAGON)

  Summary:

  This is 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 is divided into 3 treatment parts (Part A1, Part A2, and Part B) and a Long-Term Extension Phase (LTEP).

  Objective:

  Part A1 Dose Escalation: Single-Agent SRK-181 Primary: - Evaluate the safety and tolerability of single-agent SRK-181. - Determine the MTD or MAD, and the RP2D of SRK-181 and evaluate DLTs of single-agent SRK-181. Secondary: - Evaluate the PK of SRK-181 as a single agent. - Evaluate the incidence and persistence of anti-SRK-181 antibody formation and its impact on the PK profile of SRK-181. Part A2 Dose Escalation: SRK-181 in Combination with Anti-PD-(L)1 Antibody Therapy Primary: - Evaluate the safety and tolerability of SRK-181 in combination with anti-PD-(L)1 antibody therapy. - Determine the MTD or MAD, and the RP2D of SRK-181 in combination with anti-PD-(L)1 antibody therapy and evaluate DLTs of SRK-181 in combination with anti-PD-(L)1 antibody therapy. Secondary: - Evaluate the PK of SRK-181 when in combination with anti-PD-(L)1 antibody therapy. - Evaluate the incidence and persistence of anti-SRK-181 antibody formation and its impact on the PK profile of SRK-181 when in combination with anti-PD-(L)1 antibody therapy. - Evaluate the PK of anti-PD-(L)1 antibody therapy. - Evaluate the incidence and persistence of anti-drug antibody (ADA) formation against anti-PD-(L)1 and its impact on the PK profile of anti-PD-(L)1 when in combination with SRK-181 antibody therapy. Part B Dose Expansion: SRK-181 in Combination with Anti-PD-(L)1 Antibody Therapy Primary: - Evaluate the safety and tolerability of SRK-181 in combination with anti-PD-(L)1 antibody therapy in 4 expansion cohorts, including: - Cohort A: NSCLC (anti-PD-(L)1 antibody therapy in this cohort is pembrolizumab) - Cohort B: UC (anti-PD-(L)1 antibody therapy in this cohort is pembrolizumab) - Cohort C: MEL (anti-PD-(L)1 antibody therapy in this cohort is pembrolizumab) - Cohort D: Any other advanced or metastatic solid tumor type that is not NSCLC, UC, or MEL. (Anti-PD-(L)1 antibody therapy in this cohort is the patient s current approved anti-PD-(L)1 antibody therapy.) Secondary: - Evaluate the anti-tumor activity (including but not limited to BOR, ORR, DoR, and DCR) of SRK-181 in combination with anti-PD-(L)1 antibody therapy. - Evaluate the PK of SRK-181 when in combination with anti-PD-(L)1 antibody therapy. - Evaluate the incidence and persistence of anti-SRK-181 antibody formation in combination with anti-PD-(L)1 antibody therapy. - Evaluate the PK of anti-PD-(L)1 antibody therapy. - Evaluate the incidence and persistence of ADA formation against anti-PD-(L)1 and its impact on the PK profile of anti-PD-(L)1 when in combination with SRK-181 antibody therapy.

• Treatments

  Therapies:

  Immunotherapy

  Medications:

  Atezolizumab (Tecentriq); BMS-936558 (Nivolumab); Cemiplimab (); Nivolumab (Opdivo); Pembrolizumab (Keytruda); REGN2810 (Cemiplimab); SRK-181 ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • 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:
  • 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 from all prior anti-PD-1 therapies (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. If the anti-PD-1 therapy is used in adjuvant setting, patients must have had disease progression clinically or radiographically on the anti-PD-1 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: (a) Patients must have a histologically confirmed diagnosis of recurrent or metastatic HNSCC that is non-amendable to curative therapy (e.g., radiation or surgery). (b) The primary tumor location must be the oropharynx, oral cavity, hypopharynx, or larynx. Primary tumor site of nasopharynx (any histology) or unknown primary tumor are not eligible. (c) Patients must have received one prior line of anti-PD-1 treatment (alone or in combination with other therapy) and have had disease progression clinically or radiographically on the anti-PD-1 treatment. (d) Up to one line of treatment are allowed between the last dose of anti-PD-1 and enrollment. (e) For patients with primary oropharyngeal cancer, patients must have results from testing of human papillomavirus (HPV) or P16 status. Other criteria apply

• Exclusion Criteria

  Key Exclusion Criteria: For Part A1 only:
  • Patient has had anti-PD-(L)1 antibody therapy ≤ 28 days prior to the first dose of SRK-181. 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-181. 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-181.
  • Patient has received biologic therapy (except for anti-PD-(L)1 antibody therapy for Part A2 or Part B), > Patient has received systemic cytotoxic chemotherapy (except for in combination with anti-PD-(L)1 antibody therapy) > Patient has received targeted small molecule therapy within 5 half-lives of the compound prior to the first dose of SRK-181.
  • 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.
  • Patient has the documented presence of neutralizing ADA to anti-PD-(L)1 antibody therapy.
  • Patient has a diagnosis of immunodeficiency, either primary or acquired.
  • Patient is symptomatic or has uncontrolled brain metastases, leptomeningeal disease, or spinal cord compression not definitively treated with surgery or radiation.
  • Patient has current second malignancy at other sites (exceptions: adequately treated in situ carcinoma [e.g., cervical], non-MEL skin cancer, bilateral synchronous discordant breast cancer, or indolent prostate cancer under observation). A past history of other malignancies is allowed as long as patient has been free of recurrence for ≥ 2 years, or if the patient has been treated with curative intent within the past 2 years and, in the opinion of the Investigator, is unlikely to have a recurrence.
  • Women who are pregnant or breastfeeding

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