Clinical Trial 22199-C

• Overview

  Study Title:

  TACTIVE-U: An Interventional Safety and Efficacy Phase 1b/2, Open-Label Umbrella Study to Investigate Tolerability, PK, and Antitumor Activity of Vepdegestrant (ARV-471/PF-07850327), an Oral Proteolysis Targeting Chimera, in Combination with Other Anticancer Treatments in Participants Aged 18 and Older with ER+ Advanced or Metastatic Breast Cancer, Sub-Study C (ARV-471 in Combination with Samuraciclib)

  Summary:

  The purpose of this study is to learn about the safety and effects of the study medicine called vepdegestrant. Vepdegestrant is studied to see if it can be a possible treatment for advanced metastatic breast cancer. This type of cancer would have spread from where it started (breast) to other parts of the body and would be tough to treat.

  Objective:

  Phase 1b Primary: * To assess safety and tolerability of ARV-471 in combination with samuraciclib in participants with ER+/HER2- A/MBC to select up to 2 RDEs for the combination. Phase 1b Secondary: * To evaluate the overall safety profile. * To evaluate antitumor activity of ARV-471 in combination with samuraciclib. * To evaluate the plasma exposure of ARV-471, ARV-473, and samuraciclib when ARV-471 and samuraciclib are given in combination. Phase 2 Primary: * To assess the clinical antitumor activity of ARV-471 in combination with samuraciclib. Phase 2 Secondary: * To determine additional antitumor activity outcomes of ARV-471 in combination with samuraciclib. * To further characterize the overall safety profile and tolerability of ARV-471 in combination with samuraciclib. * To evaluate the plasma exposure of ARV-471, ARV-473 and samuraciclib when ARV-471 and samuraciclib are given in combination. * To assess changes from baseline levels in plasma ctDNA with treatment. * To evaluate the correlation between TP53 mutation status and antitumor activity.

• Treatments

  Therapies:

  Therapy (NOS)

  Medications:

  ARV-471 (); Samuraciclib ()

• Inclusion Criteria

  Inclusion Criteria:
  • Histological or cytological diagnosis of breast cancer. At time of enrollment this must not be amendable to surgical resection with curative intent (1% or greater ER+ stained cells as per local practice on the most recent tumor biopsy HER2- tumor by IHC or in-situ hybridization per ASCO/CAP).
  • Prior anticancer therapies: up to 2 lines of prior therapies for advanced/metastatic disease; 1 line of any CDK4/6 inhibitor-based regimen is required (in any setting eg adjuvant, metastatic) at least 1 measurable lesion as defined by RECIST v1.1.
  • Eastern Cooperative Oncology Group Performance Status (ECOG) (PS) 1 or less.

• Exclusion Criteria

  Exclusion Criteria:
  • Visceral crisis at risk of life-threatening complications in the short term
  • Known history of drug-induced pneumonitis or other significant symptomatic deterioration of lung functions.
  • Newly diagnosed brain metastases, or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated, clinically stable and discontinued anti-seizure medications and corticosteroids for at least 28 days prior to enrollment in the of study.
  • History of any other tumor malignancies within the past 3 years, except for the following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated in situ carcinoma of the cervix.
  • Inflammatory breast cancer
  • Impaired cardiovascular function or clinically significant cardiovascular diseases
  • Concurrent administration of medications, food, or herb supplements that are strong inhibitors/inducers of CYP3A, strong CYP2D6 inhibitors and drugs known to predispose to Torsade de Pointes or QT interval prolongation.
  • Renal impairment, not adequate liver function and/or bone marrow function
  • Known active infection

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