Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: ALRN-6924 and Paclitaxel in Treating Patients With Advanced, Metastatic, or Unresectable Solid Tumors

Summary: There are 2 parts to this clinical research study: Part 1 (dose escalation) and Part 2 (dose expansion).
  The goal of Part 1 of this clinical research study is to find the highest tolerable dose of ALRN-6924 in combination with paclitaxel that can be given to patients who have advanced solid cancers with a specific normal protein, p53. The p53 protein helps control the growth of cancer cells.
  The goal of Part 2 of this study is to learn if the dose of ALRN-6924 in combination with paclitaxel found in Part 1 can help to control advanced cancer in patients who have a specific mutation (genetic change).
  The safety of this drug combination will also be studied.
  This is an investigational study. ALRN-6924 is not FDA approved or commercially available. It is currently being used for research purposes only. Paclitaxel is FDA approved and commercially available for the treatment of many types of cancer, including the type of cancer you have. It is considered investigational to combine ALRN-6924 and paclitaxel.
  The study doctor can explain how the study drugs are designed to work.
  Up to 45 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description: Objectives:
  Primary Objectives:
  Determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of ALRN-6924 in combination with paclitaxel in adult patients with advanced or metastatic solid tumors with wild-type (WT) TP53.
  Evaluate the safety and tolerability of ALRN-6924 in combination with paclitaxel in patients with advanced or metastatic WT TP53 solid tumors.
  Key Secondary Objective:
  Evaluate the anti-tumor activity of ALRN-6924 in combination with paclitaxel in solid tumors (in dose escalation) and hormone-receptor positive breast cancer (in expansion).
  Other Secondary Objectives:
  Describe the pharmacokinetics (PK) of ALRN-6924 and paclitaxel in plasma following single and multiple intravenous (IV) infusions (Cycle 1 Day 1, D2, D15 and Cycle 2 D1).

Eligibility: Inclusion Criteria:
  1. 18 years of age or older
  2. Histologically- or cytologically-confirmed solid tumors (excluding lymphomas) that are metastatic or unresectable and that meet the following criteria: a) Escalation and expansion cohorts: wild type (WT) TP53 status defined as no mutation on a Clinical Laboratory Improvement Amendments (CLIA)-certified next-generation sequencing (NGS) assay that has sequenced the full length TP53 gene. Patients can be enrolled based on tissue testing or liquid biopsies. If enrolled based on liquid biopsies, testing should have detected other somatic mutations;
  3. (CONT) b) Expansion cohort only: estrogen receptor (ER) positive (> 1%), human epidermal growth factor 2 (HER2) negative, WT TP53 metastatic or inoperable locally advanced or locally recurrent breast cancer, regardless of progesterone receptor (PR) status HER2 status will be defined according to the ASCO/CAP 2018 recommendation (Patients can be HER2 0+ or 1+ by immunohistochemistry (IHC), 2+ by IHC and fluorescent in situ hybridization (FISH) non-amplified to be considered HER2 negative).
  4. Standard treatment with therapies known to confer a survival benefit does not exist, is no longer effective or tolerated, or the patient declines standard treatment. For the dose expansion cohort only, breast cancer patients with ER+, HER2- status must have received prior endocrine therapy and CDK4/6 inhibitors.
  5. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. In the dose escalation stage, patients without measurable disease by RECIST 1.1, but evaluable disease are also eligible.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  7. Demonstrate adequate organ function as defined by the parameters listed below: a) Serum creatinine </= 1.5 x upper limit of normal (ULN) or >/= 45 mL/min/1.73m2 by CKD-EPI equation for subjects with creatinine levels > 1.5 x institutional ULN; b) Total bilirubin </= 1.5 x ULN, or direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5 x ULN, or unless due to Gilbert's Syndrome; c) Alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) </= 2.5 x ULN or </= 5 x ULN if hepatic abnormalities are related to underlying liver metastases or liver/biliary primary; d) Absolute neutrophil count (ANC) >/=1500/mm3(without GCSF in the 2 weeks prior to treatment start); e)Platelet count >/= 100,000/mm3; f) Hemoglobin >/= 9 g/dL (without blood transfusion in the 2 weeks prior to treatment start); g) International normalized ratio (INR) and activated partial thromboplastin time (aPTT) </= 1.5 x ULN.
  8. All patients (males and females) of childbearing potential must agree to use medically effective contraception during the study and for 6 months after the last dose of study drugs. Females must have a negative serum pregnancy test during screening and a negative urine pregnancy test at study day 1 prior to initiation of treatment.
  9. Have no concomitant medical condition (including, but not limited to, ongoing or active infection or any psychiatric disorder), that in the judgment of the investigator will interfere with the patient's ability to participate in the study or render such participation medically inappropriate.
  10. No medical history of another cancer (except basal or squamous cell skin cancer or in situ cervical cancer, or carcinomas in situ or other malignancies with a >/=95% 5-year survival) within 2 years of the start of study treatment.
  11. No investigational drug or other anticancer treatments (including chemotherapy or radiation therapy) within 21 days or at least 5 half-lives, whichever is shorter, of the start of the study treatment.
  12. No major surgery within 1 month of treatment and fully recovered.
  13. Willing and able to provide informed consent.
  Exclusion Criteria:
  1. Previous treatment with investigational agents that inhibit MDM2 or MDMX activity.
  2. Known active hepatitis B, hepatitis C and/or human immunodeficiency virus (HIV)-positive patients who have a cluster of differentiation 4 (CD4) count < 200. No antiretroviral medications that are CYP3A4 substrates will be allowed.
  3. Requirement for therapeutic anticoagulation
  4. Pre-existing history of or known cardiovascular risk: a) History of acute coronary syndromes within 6 months prior to the first dose of ALRN-6924 (including myocardial infarction, unstable angina, coronary artery bypass graft, angioplasty, or stenting); b) Uncontrolled hypertension; c) Pre-existing cardiac failure (New York Heart Association class III-IV); d) Atrial fibrillation on anti-coagulants; e) Clinically significant uncontrolled arrhythmias; f) Corrected QTcF interval on screening electrocardiography (ECG) >/=450 msec for males and >/=470 msec for females (QTcF >480 msec for any patient with a bundle branch block).
  5. Clinically significant gastrointestinal bleeding within 6 months prior to the start of study treatment.
  6. Females who are pregnant or nursing.
  7. Symptomatic central nervous system (CNS) metastases by history, clinical signs or radiologic findings. Stable brain metastases (1 month after completion of treatment) confirmed by imaging are allowed.
  8. Known hypersensitivity to any study drug component.
  9. The required use of any concomitant medications that are predominantly cleared by hepatobiliary transporters, Organic-anion-transporting polypeptide (OATP) members OATP1B1 and OATP1B3, on the day of the ALRN-6924 infusion or within 48 hours after an ALRN-6924 infusion.
  10. Patients with Grade >/=2 neuropathy will be excluded.

Relevance to patient case: not relevant