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

• ClinicalTrials.gov Identifier: NCT03725436
• Recruitment Status: Recruiting
• First Posted: October 31, 2018
• Last Update Posted: August 26, 2022
• Sponsor: M.D. Anderson Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Advanced Malignant Solid Neoplasm; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Estrogen Receptor Positive; HER2/Neu Negative; Metastatic Malignant Solid Neoplasm; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8; Recurrent Breast Carcinoma; TP53 wt Allele; Unresectable Malignant Solid Neoplasm	Drug: MDM2/MDMX Inhibitor ALRN-6924; Drug: Paclitaxel	Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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).

EXPLORATORY OBJECTIVES:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b Study of ALRN-6924 in Combination With Paclitaxel in Wild-Type TP53 Advanced or Metastatic Solid Tumors Including Estrogen-Receptor Positive Breast Cancer
• Actual Study Start Date: January 24, 2019
• Estimated Primary Completion Date: July 26, 2023
• Estimated Study Completion Date: July 26, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (paclitaxel, ALRN-6924); Patients receive paclitaxel 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.	Drug: MDM2/MDMX Inhibitor ALRN-6924; Given IV; Other Name: ALRN-6924; Drug: Paclitaxel; Given IV; Other Names: Anzatax; Asotax; Bristaxol; Praxel; Taxol; Taxol Konzentrat

Outcome Measures

Primary Outcome Measures :

1. Maximum tolerated dose (MTD) of combination of ALRN-6924 and paclitaxel, defined as the isotonic estimate of the toxicity rate closest to 0.30 [ Time Frame: Up to 28 days ]

Secondary Outcome Measures :

1. Objective response rate (ORR) defined as the proportion of patients with complete response (CR) or partial response (PR), as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) [ Time Frame: Up to 4 years ]
   Descriptive statistics will be used to summarize all patient data. When applicable, t-tests or Wilcoxon rank-sum tests will be used to make comparisons between patient subgroups of interest for continuous variables for parametric and non-parametric outcomes, respectively. Categorical data will be summarized using frequencies and percentages. Chi-square tests or Fisher's exact tests will be used to make comparisons between patient subgroups of interest for categorical variables. Will be estimated for the expansion cohort of 15 patients treated at the MTD, with corresponding exact 95% confidence intervals.
2. Duration of response (DoR) [ Time Frame: Time from documentation of tumor response to disease progression, assessed up to 4 years ]
   Descriptive statistics will be used to summarize all patient data. When applicable, t-tests or Wilcoxon rank-sum tests will be used to make comparisons between patient subgroups of interest for continuous variables for parametric and non-parametric outcomes, respectively. Categorical data will be summarized using frequencies and percentages. Chi-square tests or Fisher's exact tests will be used to make comparisons between patient subgroups of interest for categorical variables. Median DoR will be presented with corresponding Kaplan-Meier curves.
3. Progression-free survival (PFS) [ Time Frame: Time from the start of treatment to disease progression or death, whichever occurs first, assessed up to 4 years ]
   Descriptive statistics will be used to summarize all patient data. When applicable, t-tests or Wilcoxon rank-sum tests will be used to make comparisons between patient subgroups of interest for continuous variables for parametric and non-parametric outcomes, respectively. Categorical data will be summarized using frequencies and percentages. Chi-square tests or Fisher's exact tests will be used to make comparisons between patient subgroups of interest for categorical variables. Median PFS will be presented with corresponding Kaplan-Meier curves.
4. Clinical benefit rate [ Time Frame: At 24 weeks ]
   Will be defined as the proportion of patients with CR, PR, or stable disease (SD). Descriptive statistics will be used to summarize all patient data. When applicable, t-tests or Wilcoxon rank-sum tests will be used to make comparisons between patient subgroups of interest for continuous variables for parametric and non-parametric outcomes, respectively. Categorical data will be summarized using frequencies and percentages. Chi-square tests or Fisher's exact tests will be used to make comparisons between patient subgroups of interest for categorical variables.
5. Overall survival (OS) [ Time Frame: Time from the start of treatment to death from any cause, assessed up to 4 years ]
   Descriptive statistics will be used to summarize all patient data. When applicable, t-tests or Wilcoxon rank-sum tests will be used to make comparisons between patient subgroups of interest for continuous variables for parametric and non-parametric outcomes, respectively. Categorical data will be summarized using frequencies and percentages. Chi-square tests or Fisher's exact tests will be used to make comparisons between patient subgroups of interest for categorical variables.
6. Pharmacokinetics parameters [ Time Frame: Up to 4 years ]
   Will assess area under the curve (AUC).

Other Outcome Measures:

1. Response [ Time Frame: Up to 4 years ]
   Will assess correlation of response with p53 status, p21 status, murine double minute 2 (MDM2) and murine double minute X (MDMX) expression by immunohistochemistry (IHC) and by reverse phase proteomic array (RPPA) in pre- and on-treatment tumor biopsy samples.
2. Gene mutations [ Time Frame: Up to 4 years ]
   Will use whole exome sequencing on pre-treatment biopsy and at progression for TP53 mutations, MDM2 and MDMX copy number and other genomic alterations.
3. Gene expression profiling [ Time Frame: Up to 4 years ]
   Will use ribonucleic acid sequencing for gene expression profiling pre-treatment, on-treatment and at progression.
4. Cell proliferation and apoptosis assays [ Time Frame: Up to 4 years ]
   Will apply cell proliferation and apoptosis assays (Ki67, cleaved caspase3) on pre- and on-treatment tumor biopsy samples.
5. Cell-free deoxyribonucleic acid (DNA) [ Time Frame: Up to 4 years ]
   Will assess cell-free DNA (cfDNA) in blood, and serum concentrations of MIC-1.
6. Pharmacokinetics parameters [ Time Frame: Up to 4 years ]
   Will assess maximum concentration (Cmax)
7. Pharmacokinetics parameters [ Time Frame: up to 4 years ]
   Will assess time to Cmax (Tmax)
8. Pharmacokinetics parameters [ Time Frame: up to 4 years ]
   Will assess half-life (t1/2) for ALRN-6924 and paclitaxel.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 18 years of age or older
• 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.

Exclusion Criteria:

• 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.

Contacts and Locations

Contacts

Contact: Ecaterina E Dumbrava; 713-792-3934; EEIleana@mdanderson.org

Locations

United States, Texas

M D Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Ecaterina E Dumbrava 713-792-3934

Principal Investigator: Ecaterina E Dumbrava

Sponsors and Collaborators

M.D. Anderson Cancer Center

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ecaterina E Dumbrava; M.D. Anderson Cancer Center

More Information

Additional Information:

MD Anderson Cancer Center 

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT03725436
• Other Study ID Numbers: 2018-0561; NCI-2018-02192 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2018-0561 ( Other Identifier: M D Anderson Cancer Center )
• First Posted: October 31, 2018
• Last Update Posted: August 26, 2022
• Last Verified: August 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Paclitaxel; Albumin-Bound Paclitaxel; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action