Clinical Trials /

PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery

NCT03218826

Description:

This phase I trial studies the side effects and best dose of PI3Kbeta inhibitor AZD8186 when given together with docetaxel in treating patients with solid tumors with PTEN or PIK3CB mutations that have spread to other places in the body or cannot be removed by surgery. PI3Kbeta inhibitor AZD8186 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, 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. Giving PI3Kbeta inhibitor AZD8186 and docetaxel may work better in treating patients with solid tumors.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PI3Kbeta Inhibitor AZD8186 and Docetaxel in Treating Patients Advanced Solid Tumors With PTEN or PIK3CB Mutations That Are Metastatic or Cannot Be Removed by Surgery
  • Official Title: Phase I Study of AZD8186 in Combination With Docetaxel in Patients With PTEN Mutated or PIK3CB Mutated Advanced Solid Tumors, Potentially Amenable to Docetaxel

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01232
  • SECONDARY ID: NCI-2017-01232
  • SECONDARY ID: 10131
  • SECONDARY ID: 10131
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT03218826

Conditions

  • Advanced Malignant Solid Neoplasm
  • Estrogen Receptor Negative
  • Estrogen Receptor Positive
  • HER2/Neu Negative
  • Metastatic Malignant Solid Neoplasm
  • Progesterone Receptor Negative
  • PTEN Gene Mutation
  • Triple-Negative Breast Carcinoma
  • Unresectable Solid Neoplasm

Interventions

DrugSynonymsArms
DocetaxelDocecad, RP56976, Taxotere, Taxotere Injection ConcentrateTreatment (docetaxel, PI3Kbeta inhibitor AZD8186)
PI3Kbeta Inhibitor AZD8186AZD-8186, AZD8186Treatment (docetaxel, PI3Kbeta inhibitor AZD8186)

Purpose

This phase I trial studies the side effects and best dose of PI3Kbeta inhibitor AZD8186 when given together with docetaxel in treating patients with solid tumors with PTEN or PIK3CB mutations that have spread to other places in the body or cannot be removed by surgery. PI3Kbeta inhibitor AZD8186 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, 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. Giving PI3Kbeta inhibitor AZD8186 and docetaxel may work better in treating patients with solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of
      PI3Kbeta inhibitor AZD8186 (AZD8186) when administered in combination with docetaxel in
      patients with PTEN or PIK3CB mutated advanced solid tumors.

      II. To assess the safety and tolerability of AZD8186 when administered in combination with
      docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.

      SECONDARY OBJECTIVES I. To observe and record anti-tumor activity. II. To assess the
      objective response rate (ORR) of AZD8186 when administered in combination with docetaxel in
      patients with PTEN or PIK3CB mutated advanced solid tumors.

      III. To assess the clinical benefit rate at 24 weeks of AZD8186 when administered in
      combination with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.

      IV. To investigate a drug-drug interaction between docetaxel and AZD8186 and correlate drug
      exposure with pharmacodynamics response.

      TERTIARY OBJECTIVES:

      I. Examine the pattern of co-mutated genes in PTEN or PIK3CB mutated tumors and their
      association with treatment response or resistance.

      II. Describe possible mechanisms of acquired resistance to PI3Kbeta inhibition. III.
      Evaluation of protein expression of the PTEN gene and its association with treatment response
      or resistance.

      IV. Examine isoform-specific AKT inhibition and other downstream target modulation from
      PI3Kbeta inhibition with AZD8186.

      OUTLINE: This is a dose-escalation study of PI3Kbeta inhibitor AZD8186.

      Patients receive docetaxel intravenously (IV) over 1 hour on day 1 and PI3Kbeta inhibitor
      AZD8186 orally (PO) twice daily (BID) for 5 days each week. Courses repeat every 21 days in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days and then every 3
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (docetaxel, PI3Kbeta inhibitor AZD8186)ExperimentalPatients receive docetaxel IV over 1 hour on day 1 and PI3Kbeta inhibitor AZD8186 PO BID for 5 days each week. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Docetaxel
  • PI3Kbeta Inhibitor AZD8186

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed malignancy that is metastatic or
             unresectable and for which standard curative or palliative measures do not exist or
             are no longer effective

          -  Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest
             x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance
             imaging (MRI), or calipers by clinical exam; (pharmacodynamic and disease specific
             expansion cohorts only)

          -  Measurable disease will not be required for enrollment in the dose escalation cohort

          -  Unlimited prior therapies allowed

          -  Docetaxel appropriate

               -  May have previously received docetaxel, if anticipated to have maintained taxane
                  sensitivity (for the dose escalation cohort only)

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin within normal institutional limits (patients with confirmed Gilbert's
             syndrome with a total bilirubin =< 2.0 x upper limit of normal [ULN], may be included
             in this study)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 1.5 x institutional upper limit of normal

          -  Creatinine within normal institutional limits OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

          -  PTEN or PIK3CB mutated advanced solid tumor

               -  PTEN loss of function mutation or PIK3CB gain of function mutation identified by
                  local Clinical Laboratory Improvement Act (CLIA) certified next generation
                  sequencing (NGS)

               -  Breast cancers patients enrolled on this study must have either:

                    -  Estrogen receptor positive and HER2 negative breast cancer

                    -  Triple negative breast cancer

          -  Adequate archival tissue (metastatic tissue sample is preferable but primary tumor
             tissue will be acceptable) or willing to undergo pre-treatment biopsy (for central
             confirmation of molecular alteration and PTEN immunohistochemical assessment) if
             adequate archival tissue is unavailable

          -  Consent to allow mandatory paired (pre- and on- treatment) fresh tissue biopsies if
             deemed safe to do so for quantitation of Akt pathway signaling proteins
             (pharmacodynamic expansion cohort only)

          -  Women of child-bearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation; should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately; men treated or enrolled on this protocol must also
             agree to use adequate contraception prior to the study, for the duration of study
             participation, and 4 months after completion of AZD8186 administration

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  HER2 positive breast cancer

          -  Prior treatment with PI3K/AKT inhibitors

          -  Any known concurrent RAF or PIK3CA mutation

          -  Patients who have had chemotherapy, radiotherapy, immunotherapy or anticancer agents
             within 4 weeks (6 weeks for nitrosoureas or mitomycin C) of the first dose of study
             treatment, except hormonal therapy with luteinizing hormone-releasing hormone (LHRH)
             analogues for medical castration in patients with prostate cancer and breast cancer,
             which are permitted

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1)

          -  Patients who are receiving any other investigational agents

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to AZD8186 or docetaxel

          -  Patients receiving any medications or substances that are strong inhibitors and/or
             strong or moderate inducers of CYP3A4 are ineligible

          -  Existing bleeding or condition associated with increased risk of bleeding (including
             requirement for chronic anticoagulation)

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, uncontrolled hypertension, symptomatic congestive heart failure, unstable
             angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements

          -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with AZD8186; these potential risks may also apply to other
             agents used in this study

          -  HIV-patients positive for human immunodeficiency virus (HIV) are NOT excluded from
             this study, but Human immunodeficiency virus (HIV)-positive patients must have:

               -  A stable regimen of highly active anti-retroviral therapy (HAART) that does not
                  include strong inhibitors and strong or moderate inducers of CYP3A4

               -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                  of opportunistic infections

               -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                  polymerase chain reaction (PCR)-based test
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Patient safety and tolerability will be described according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. All patients who receive any amount of the study drug will be evaluable for toxicity.

Secondary Outcome Measures

Measure:Clinical benefit rate (CBR) defined as complete response (CR), partial response (PR), or stable disease assessed by modified Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:At 24 weeks
Safety Issue:
Description:Will assess the CBR of PI3Kbeta inhibitor AZD8186 when administered in combination with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors. A 90% confidence interval on CBR will be calculated assuming binomial proportions.
Measure:Drug-drug interaction between docetaxel and PI3Kbeta inhibitor AZD8186
Time Frame:Up to 2 years
Safety Issue:
Description:Will investigate a drug-drug interaction between docetaxel and PI3Kbeta inhibitor AZD8186 and correlate drug exposure with pharmacodynamics response.
Measure:Objective response rate (ORR)
Time Frame:At 24 weeks
Safety Issue:
Description:Will assess the objective response rate (ORR) of PI3Kbeta inhibitor AZD8186 when administered in combination with docetaxel in patients with PTEN or PIK3CB mutated advanced solid tumors.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 4, 2017