Clinical Trials /

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

NCT03725436

Description:

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.

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 2018-0561
  • SECONDARY ID: NCI-2018-02192
  • SECONDARY ID: 2018-0561
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03725436

Conditions

  • 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

Interventions

DrugSynonymsArms
MDM2/MDMX Inhibitor ALRN-6924ALRN-6924Treatment (paclitaxel, ALRN-6924)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (paclitaxel, ALRN-6924)

Purpose

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 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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (paclitaxel, ALRN-6924)ExperimentalPatients 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.
  • MDM2/MDMX Inhibitor ALRN-6924
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.
Measure:Duration of response (DoR)
Time Frame:Time from documentation of tumor response to disease progression, assessed up to 4 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Clinical benefit rate
Time Frame:At 24 weeks
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Time from the start of treatment to death from any cause, assessed up to 4 years
Safety Issue:
Description: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.
Measure:Pharmacokinetics parameters
Time Frame:Up to 4 years
Safety Issue:
Description:Will assess area under the curve (AUC).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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