A Study of ALRN-6924 for Protection of Chemotherapy-Induced Side Effects in Patients With TP53-Mutant Breast Cancer

This is a Phase 1b open-label, single arm, multicenter, study of ALRN-6924 as a chemoprotection agent in patients with TP53-mutated HER2- breast cancer (stages IIa to IIIb) receiving neoadjuvant or adjuvant chemotherapy with doxorubicin, docetaxel, and cyclophosphamide (TAC). Chemotherapy affects cells that are dividing, whether they are tumor cells or healthy cells (including, bone marrow cells, hair follicle cells, and epithelial cells lining the gastrointestinal tract). ALRN-6924 is designed to stop cell division in healthy cells but not in tumor cells because they have a mutation of the TP53 gene. When this happens, tumor cells will still be destroyed by the chemotherapy but healthy cells that are not dividing may be spared from chemotherapy damage and the patient should have less side effects.

This is a Phase 1b, open-label, single-arm, multicenter clinical trial for evaluation of safety, tolerability and chemoprotection effects of ALRN-6924 combined with chemotherapy in patients with TP53-mutated, HER2 negative breast cancer without distant organ metastases. All patients will receive the neoadjuvant or adjuvant chemotherapy regimen known as TAC. TAC consists of doxorubicin 50 mg/m2 IV infusion, docetaxel 75mg/m2 IV infusion and cyclophosphamide 500 mg/m2 IV infusion, given on Day 1 of every 3-week cycle for a total of 4-6 treatment cycles according to each patient's individual needs, individual institutional policies and standards of care, as well as investigator discretion. ALRN-6924 1.2 mg/kg will be administered on 3 consecutive days in each treatment cycle, Days 0-2. Prophylactic administration of G-CSF prior to the first instance of Grade 4 neutropenia is not allowed in Cycle 1. Myeloid growth factor support with filgrastim should be administered immediately if a patient is diagnosed with Grade 4 neutropenia.

Eligibility Criteria:
Inclusion Criteria:

* Females and males, age ≥18years.
* Patients who, in the investigator's judgment, are able to understand and willing to comply with the requirements of this clinical trial and to provide written informed consent.
* Histologically confirmed diagnosis of HER2 negative breast cancer
* Candidate to receive chemotherapy with TAC regimen
* Presence of p53 mutation(s) in tumor tissue as assessed by next generation sequencing (NGS).
* Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤2
* Left ventricular ejection fraction \> 55%.
* Laboratory results obtained within 14 days prior to the first study treatment administration (Cycle 1, Day 0) demonstrating:

  * Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte colony stimulating factor \[G-CSF\] support within 2 weeks prior to the first study treatment administration)
  * Platelet count ≥ 100,000/μL (without transfusion within 2 weeks prior to the first study treatment administration)
  * Hemoglobin ≥ 10.0 g/dL
  * AST, ALT, and alkaline phosphatase ≤ 2.5 x the upper limit of normal (ULN)
  * Serum bilirubin ≤ 1.5× ULN (patients with known Gilbert's disease who have serum bilirubin level ≤ 3× ULN may be enrolled.)
  * Patients who are not receiving therapeutic anticoagulation: Calculated creatinine clearance (CrCl) ≥ 30 mL/min (Cockcroft-Gault formula).
* Have not received prior chemotherapy or targeted systemic therapy for their breast cancer.

Exclusion Criteria:

* Known hypersensitivity to any component of study treatment.
* Prior chemotherapy for HER2 negative breast cancer.

  1. Presence of distant metastases. Nodal involvement is acceptable.
* Uncontrolled intercurrent illness including but not limited to:

  * Clinically significant, active, uncontrolled infection including human immunodeficiency virus (HIV), or hepatitis B or C

    * Patients with HIV must be on effective antiretroviral therapy for ≥ 4 weeks prior to enrollment and have HIV viral load \< 400 copies/mL, have had no acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the past 12 months, and have CD4+ count ≥ 350 cells/μL.
    * Patients with chronic hepatitis B virus (HBV) must be on antiviral therapy and have HBV viral load below the limits of detection.
    * Patients with hepatitis C virus (HCV) must be on or have completed antiviral therapy and have an HCV viral load below the limits of detection.
  * Uncontrolled hypertension
  * Uncontrolled diabetes mellitus
* Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker.
* Pregnant or lactating women.
* Hereditary angioedema of any severity or severe or life-threatening angioedema due to any cause.
* Treatment with an investigational agent for any indication within the shorter of 14 days or 5 half-lives, if the half-life is known.
* The required use of any concomitant medications that are predominantly cleared by hepatobiliary transporters, OATP members OATP1B1 and OATP1B3, on the day of the first ALRN-6924 infusion to within 48 hours after the last ALRN-6924 infusion in a treatment cycle. This criterion does not apply to the patients in the control group.
* Other medications, severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.
* Clinically evident alopecia of any grade at screening.