ALRN-6924 and Paclitaxel in Treating Patients with Advanced, Metastatic, or Unresectable Solid Tumors
This phase Ib trial studies the side effects and best dose of ALRN-6924 when given together with paclitaxel in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery. Drugs used in chemotherapy, such as ALRN-6924 and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.
- 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; 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. Patients can be HER2 0+ or 1+, 2+ or FISH non-amplified to be considered HER2 negative.
- 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.
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or >= 45 mL/min/1.73 m^2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for subjects with creatinine levels > 1.5 x institutional ULN.
- 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.
- 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.
- Absolute neutrophil count (ANC) >=1500/mm^3 (without granulocyte-colony stimulating factor [GCSF] in the 2 weeks prior to treatment start).
- Platelet count >= 100,000/mm^3.
- Hemoglobin >= 9 g/dL (without blood transfusion in the 2 weeks prior to treatment start).
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN.
- 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.
- Have no concomitant medical condition 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.
- 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.
- 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.
- No major surgery within 1 month of treatment and fully recovered.
- Willing and able to provide informed consent.
- Previous treatment with investigational agents that inhibit MDM2 or MDMX activity.
- 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.
- Requirement for therapeutic anticoagulation.
- 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).
- Clinically significant gastrointestinal bleeding within 6 months prior to the start of study treatment.
- Females who are pregnant or nursing.
- 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.
- Known hypersensitivity to any study drug component.
- 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.
- Patients with grade >= 2 neuropathy will be excluded.
Locations & Contacts
Contact: Funda Meric-Bernstam
Trial Objectives and Outline
I. Determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of MDM2/MDMX inhibitor ALRN-6924 (ALRN-6924) in combination with paclitaxel in adult patients with advanced or metastatic solid tumors with wild-type (WT) TP53.
II. Evaluate the safety and tolerability of ALRN-6924 in combination with paclitaxel in patients with advanced or metastatic WT TP53 solid tumors.
I. 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).
II. Describe the pharmacokinetics (PK) of ALRN-6924 and paclitaxel in plasma following single and multiple intravenous (IV) infusions (cycle 1 day 1, day [D]2, D15 and cycle 2 D1).
I. Assess predictive and pharmacodynamic (PD) markers of response.
II. Assess the effects of ALRN-6924 and paclitaxel on cell proliferation and apoptosis.
III. Assess the effects of ALRN-6924 and paclitaxel on cell-free deoxyribonucleic acid (DNA) (cfDNA) dynamics and macrophage inhibitory cytokine-1 (MIC-1).
OUTLINE: This is a dose-escalation study of MDM2/MDMX inhibitor ALRN-6924.
Patients receive paclitaxel intravenously (IV) over 1 hour and MDM2/MDMX inhibitor ALRN-6924 IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 2 months for 1 year and then every 3 months thereafter.
Trial Phase & Type
M D Anderson Cancer Center
Secondary IDs NCI-2018-02192
Clinicaltrials.gov ID NCT03725436