Clinical Trial 22713

• Overview

  Study Title:

  A Phase 1a/b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GS-9716 as Monotherapy and in Combination with Anticancer Therapies in Patients with Solid Malignancies

  Objective:

  Primary Objective * To define the MTD or MAD and/or the RP2D of GS-9716 as monotherapy in advanced solid malignancies and to characterize the safety and tolerability of GS-9716 monotherapy. * Cohorts B1 and C1: To characterize the safety, tolerability, and to define MTD and/or RP2D of GS-9716 in combination with docetaxel in patients with mNSCLC following treatment for metastatic disease, including an immune checkpoint inhibitor and a platinum-containing chemotherapy. * Cohorts B4 and C4: To characterize the safety, tolerability, and to define MTD and/or RP2D of GS-9716 in combination with SG in patients with mTNBC who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease. Secondary Objectives * To characterize the PK of GS-9716 as monotherapy. * To characterize the PK of GS-9716 in combination with anticancer therapies. * Cohorts B1 and C1: To assess the preliminary efficacy of GS-9716 in combination with docetaxel in patients with mNSCLC. * Cohorts B4 and C4: To assess the preliminary efficacy of GS-9716 in combination with SG in patients with mTNBC who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease.

• Treatments

  Therapies:

  Antibody-Drug Conjugate; Chemotherapy (NOS); Therapy (NOS)

  Medications:

  GS-9716 (); Sacituzumab Govitecan (); Taxotere (docetaxel); docetaxel ()

• Inclusion Criteria

  Inclusion Criteria:
  • Male or female, at least 18 years of age, able to understand and give written informed consent and comply with treatment and follow-up.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Adequate hematology parameters without transfusion or growth factor support within 4 weeks prior to Cycle 1 Day 1, as demonstrated by the protocol.
  • Adequate renal function as demonstrated by creatinine clearance greater than or equal to 60 mL/min/1.73 m2 per Cockcroft-Gault and body surface area (BSA) equations; note that calculations of creatinine clearance using Modification of Diet in Renal Disease (MDRD) and other methods besides Cockcroft-Gault will not be acceptable.
  • All other toxicity at screening less than or equal to Grade 1, including peripheral neuropathy and excluding alopecia of any grade, well-controlled endocrine toxicities from prior immune checkpoint inhibitor therapy less than or equal to Grade 2, and chronic electrolyte abnormalities requiring supplementation less than or equal to Grade 2.
  • LVEF greater than or equal to 50% by transthoracic echocardiogram (TTE), as well as no clinically significant pericardial effusion on ECHO per the opinion of the investigator. Transesophageal echocardiogram (TEE) may be acceptable per discussion with the medical monitor. The same approach (TTE or TEE) must be used for a given patient throughout the study.
  • Patients with stable, treated brain metastases are eligible provided other sites of measurable disease are present and the CNS lesions are treated, nonprogressive, asymptomatic, and the patients last dose of high dose steroids (> 10 mg prednisone or equivalent) was > 4 weeks prior to Cycle 1 Day 1.
  • Patients with bone metastases currently receiving bisphosphonates for palliation will be eligible provided that other qualifying sites of measurable disease are present.
  • Women of childbearing potential must have a negative serum pregnancy test.
  • Adherence to contraception requirements per the protocol.
  • Tissue criteria: Patients must have an available, sufficient, and adequate formalin-fixed tumor tissue sample (as specified in the Laboratory Manual) from the most recently performed tumor biopsy that provides tumor tissue that meets study requirements of quantity and quality and from a site that has not been previously irradiated. Alternatively, patients must agree to have a biopsy taken prior to entering the study to provide adequate tissue. Core needle or excisional biopsy or resected tissue is required. Fine needle aspirates and bone biopsies are not acceptable.

• Exclusion Criteria

  Exclusion Criteria:
  • Prior treatment with any MCL1 inhibitor.
  • Any prior systemic investigational anticancer therapy within 28 days or 5 half-lives prior to the first dose of GS-9716, whichever is longer.
  • Any prior systemic approved anticancer therapy within 28 days or 5 half-lives prior to the first dose of GS-9716, whichever is shorter.
  • Treatment with any high-dose systemic corticosteroids within 2 weeks of the first dose of GS-9716. However, low dose corticosteroids ≤ 10 mg prednisone or equivalent daily is permitted.
  • Prior radiotherapy (or other nonsystemic therapy) within 2 weeks prior to dosing with GS-9716.
  • Women who are pregnant or lactating.
  • History of leptomeningeal disease.
  • Patients with active Grade 2 or higher nausea or vomiting, and/or signs of intestinal obstruction.
  • Known active or chronic hepatitis B or C infection or HIV infection in medical history.
  • Active hepatitis B virus (HBV) and/or active hepatitis C virus (HCV), and/or HIV infection.
  • Known history of clinically significant coronary artery disease within 12 months prior to dosing with GS-9716, including unstable angina, myocardial infarction, cardiac angioplasty, or stenting.
  • Prolonged QTc interval > 450 ms for males and > 470 ms for females.
  • Symptomatic heart failure according to New York Heart Association (NYHA) Class III or Class IV functional classification.
  • Known history of clinically significant active chronic obstructive pulmonary disease (COPD) or other moderate to severe chronic respiratory illness present within 6 months prior to dosing with GS-9716.
  • Known history of clinically significant pulmonary interstitial lung disease, active interstitial lung disease, idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (more frequently than once monthly).
  • Prior history of clinically significant bleeding, intestinal obstruction, or GI perforation within 6 months of initiation of study treatment.
  • Infection requiring IV anti-infective use within 2 weeks prior to dosing with GS-9716.
  • Active or history of autoimmune disease or immune deficiency.
  • History of uncured coexisting cancer, not including uncured basal cell carcinoma, cervical cancer in situ, or superficial bladder cancer.
  • Other concurrent medical or psychiatric conditions or any other circumstances that, in the investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
  • Unable to swallow oral tablets.

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