Clinical trial NCT05622058: A Study of ALRN-6924 for Protection of Chemotherapy-Induced Side Effects in Patients With TP53-Mutant Breast Cancer
Official title: A Phase 1b Clinical Study of the Dual MDMX/MDM2 Inhibitor, ALRN-6924, as a Chemoprotection Agent in Patients With TP53-Mutated, HER2 Negative Breast Cancer Receiving Neoadjuvant or Adjuvant Chemotherapy With Docetaxel, Doxorubicin, and Cyclophosphamide (TAC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Prevention of Chemotherapy-induced Myelosuppression
Keywords: ALRN-6924
Chemoprotection
Myelosuppression
Cell cycle arrest
p53 mutation
Breast cancer
Alopecia
Neutropenia
Lead sponsor: Aileron Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2022-11-18
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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.

Primary outcomes:
measure: Safety and tolerability of ALRN-6924 in combination with TAC chemotherapy
timeFrame: Approximately 24 weeks
measure: Chemoprotective effects of ALRN-6924 on bone marrow toxicities
timeFrame: Approximately 3 weeks for each patient
Secondary outcomes:
measure: Chemoprotective effects of ALRN-6924 on alopecia induced by TAC
timeFrame: Approximately 24 weeks
measure: Chemoprotective effects of ALRN-6924 on neutropenia
timeFrame: Approximately 24 weeks
measure: Time to absolute neutrophil count (ANC) recovery in Cycle 1
timeFrame: 3 weeks (cycle 1)
measure: Depth of ANC nadir in Cycle 1
timeFrame: 3 weeks (cycle 1)
measure: Chemoprotective effects of ALRN-6924 on Grade ≥3 neutropenia for each cycle and all cycles
timeFrame: Approximately 24 weeks
measure: Chemoprotective effects of ALRN-6924 on thrombocytopenia
timeFrame: Approximately 24 weeks
measure: Chemoprotective effects of ALRN-6924 on anemia
timeFrame: Approximately 24 weeks
measure: Chemoprotective effects of ALRN-6924 on febrile neutropenia
timeFrame: Approximately 24 weeks
measure: Chemoprotective effects of ALRN-6924 on the need for chemotherapy dose reductions
timeFrame: Approximately 24 weeks
measure: Use of myeloid growth factors
timeFrame: Approximately 24 weeks
measure: Need for red blood cell transfusions
timeFrame: Approximately 24 weeks
measure: Need for platelet transfusions
timeFrame: Approximately 24 weeks
measure: PK of ALRN-6924
timeFrame: Cycle 1 (each cycle is 21 days)
measure: PK of ALRN-6924
timeFrame: Cycle 1 (each cycle is 21 days)
measure: PK of ALRN-6924
timeFrame: Cycle 1 (each cycle is 21 days)
measure: PK of ALRN-6924
timeFrame: Cycle 1 (each cycle is 21 days)
measure: Efficacy of chemotherapy
timeFrame: Approximately 24 weeks
Other outcomes:
Locations:
city: Tamarac
country: United States
facility: Oncology and Hematology Associates of West Broward
state: Florida
city: Huntersville
country: United States
facility: Southern Oncology Specialists
state: North Carolina
city: Wilson
country: United States
facility: Regional Medical Oncolgy Center
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Gettysburg
country: United States
facility: Pennsylvania Cancer Specialists & Resesrach Institute
state: Pennsylvania
city: Banja Luka
country: Bosnia and Herzegovina
facility: University Clinical Center of the Republic of Srpska
city: Mostar
country: Bosnia and Herzegovina
facility: University Clinical Hospital Mostar
city: Sarajevo
country: Bosnia and Herzegovina
facility: Clinical Center University of Sarajevo, Oncology Clinic
city: Tuzla
country: Bosnia and Herzegovina
facility: University Clinical Center Tuzla
city: Panagyurishte
country: Bulgaria
facility: MBAL University Hospital OOD
city: Plovdiv
country: Bulgaria
facility: KOC (Complex Oncology Center) Plovdiv
city: Belgrade
country: Serbia
facility: Kliničko bolnički centar "Bežanijska kosa"
city: Kragujevac
country: Serbia
facility: Univerzitetski Klinički centar Kragujevac
city: Sremska Kamenica
country: Serbia
facility: Oncology Institute of Vojvodina
Study officials:
References: