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Phase Ib Study of Alpelisib With Cisplatin in Patients With HPV+ Solid Tumor Malignancies

NCT02620839

Description:

This phase Ib trial studies the best dose and side effects of alpelisib and cisplatin in treating patients with human papillomavirus (HPV) positive solid tumor malignancies. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, 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 alpelisib and cisplatin may work better in treating patients with solid tumor malignancies.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib Study of Alpelisib With Cisplatin in Patients With HPV+ Solid Tumor Malignancies
  • Official Title: A Phase Ib, Open-label Study of Alpelisib (BYL719) in Combination With Cisplatin in Patients With HPV+ Solid Tumor Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 159516
  • SECONDARY ID: NCI-2017-01680
  • NCT ID: NCT02620839

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
AlpelisibCohort 1A
CisplatinCohort 1A

Purpose

This phase Ib trial studies the best dose and side effects of alpelisib and cisplatin in treating patients with human papillomavirus (HPV) positive solid tumor malignancies. Alpelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, 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 alpelisib and cisplatin may work better in treating patients with solid tumor malignancies.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the maximally tolerated dose and recommended phase 2 dose of alpelisib in
      combination with weekly cisplatin.

      SECONDARY OBJECTIVES:

      I. To determine the objective response rate and median progression-free survival with the
      treatment combination in HPV positive (+) solid tumor malignancies.

      II. To characterize the safety profile of the combination.

      OUTLINE: This is a dose escalation study.

      Patients receive alpelisib orally (PO) once daily (QD) on days 1-14 or 1-21, and cisplatin
      intravenously (IV) over 1-2 hours on days 1 and 8, or days 1, 8, and 15. Courses repeat every
      21 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1AExperimentalAlpelisib: 200 mg/day, orally, days 1-21 Cisplatin: 30 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin
Cohort 2AExperimentalAlpelisib: 250 mg/day, orally, days 1-21 Cisplatin: 30 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin
Cohort 2BExperimentalAlpelisib: 250 mg/day, orally, days 1-21 Cisplatin: 35 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin
Cohort 3AExperimentalAlpelisib: 300 mg/day, orally, days 1-21 Cisplatin: 30 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin
Cohort 3BExperimentalAlpelisib: 300 mg/day, orally, days 1-21 Cisplatin: 35 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin
Cohort 4AExperimentalAlpelisib: 350 mg/day, orally, days 1-21 Cisplatin: 30 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin
Cohort 4BExperimentalAlpelisib: 350 mg/day, orally, days 1-21 Cisplatin: 35 mg/m^2, intravenously, days 1, 8, 15
  • Alpelisib
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          -  Able to understand and voluntarily sign the informed consent form, and able to comply
             with the study visit schedule and other protocol requirements. Written informed
             consent obtained prior to any screening procedures.

          -  Age ≥ 18 years.

          -  Dose escalation:

          -  Any locally advanced or metastatic solid tumor malignancy with no curative treatment
             options available

          -  Dose expansion:

          -  HPV-associated locally advanced or metastatic platinum-resistant solid tumor
             malignancy. HPV positivity defined by positive p16 immunohistochemistry or in-situ
             hybridization assessment of archival tissue (primary or metastatic) in a
             CLIA-certified laboratory. Availability of pathology report from CLIA-certified lab
             demonstrating positive HPV status by p16 IHC or in situ hybridization qualifies for
             eligibility determination. Analysis of fresh tumor tissue is permitted in cases where
             archival tissue is not available.

          -  Platinum resistance defined as prior progression (radiographic or clinical) either
             during or within 6 months following completion of platinum-based chemotherapy.

          -  Platinum-based therapy as most recent systemic therapy prior to enrollment allowed but
             not required

          -  Patients may have received any number of lines of prior systemic therapy for locally
             advanced/metastatic disease.

          -  Eastern Cooperative Oncology Group performance status ≤ 1

          -  Patient has adequate bone marrow and organ function as defined by the following
             laboratory values:

          -  Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L

          -  Platelet count ≥ 100 x 10^9/L

          -  Hemoglobin ≥ 9.0 g/dL

          -  Serum creatinine < 1.5 x ULN OR Estimated GFR by Cockroft-Gault equation OR 24 hour
             urine collection ≥ 60 ml/min

          -  Total serum bilirubin ≤ 1.5 x ULN (< 3 x ULN in patients with documented/suspected
             Gilbert's disease with concomitant direct bilirubin ≤ 1.5 x ULN)

          -  Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ 2.5 x ULN (or ≤
             5 x ULN if liver metastases are present)

          -  Fasting plasma glucose (FPG) ≤ 140mg/dL or 7.8 mmol/L

          -  Hemoglobin A1c < 7%

          -  Patient is able to swallow oral medications.

          -  Measurable or evaluable disease by RECIST 1.1 in dose escalation. Measurable disease
             by RECIST 1.1 is required in dose expansion.

          -  Recovery from all AEs of previous anti-cancer therapies, including surgery,
             chemotherapy and radiotherapy, to baseline or to CTCAE Grade ≤ 1, except for alopecia.

        Exclusion Criteria:

          -  Prior treatment with PI3K-inhibitor.

          -  Prior known hypersensitivity to any of the excipients of alpelisib.

          -  Grade ≥ 2 peripheral neuropathy.

          -  Grade ≥ sensorineural hearing loss.

          -  Patients with uncontrolled CNS metastatic involvement. However, patients with
             metastatic CNS tumors may participate in this study if the patient is:

          -  > 4 weeks from prior therapy completion (including radiation and/or surgery) to
             starting the study treatment

          -  Clinically stable with respect to the CNS tumor at the time of screening

          -  Not receiving steroid therapy

          -  Not receiving anti-convulsive medications that were started for brain metastases.

          -  Patients who have received prior systemic anti-cancer treatment within 4 weeks or 5
             half-lives of prior to starting study treatment, whichever is shorter.

          -  Prior investigational therapy within 4 weeks of start of study treatment.

          -  Patients who have received radiotherapy ≤ 2 weeks prior to starting study drugs, with
             exception of palliative radiotherapy, who have not recovered from side effects of such
             therapy to baseline or Grade ≤ 1 and/or from whom ≥ 30% of the bone marrow was
             irradiated.

          -  Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for
             treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight
             heparin (LMWH), or fondaparinux is allowed

          -  Patients who have undergone major surgery ≤ 4 weeks prior to starting study treatment
             or who have not recovered from side effects of such procedure.

          -  Clinically significant cardiac disease or impaired cardiac function, such as:

          -  Congestive heart failure (CHF) requiring treatment (New York Heart Association (NYHA)
             Grade ≥ 2) or left ventricular ejection fraction (LVEF) < 50% as determined by
             multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) at screening

          -  History or current evidence of clinically significant cardiac arrhythmias, atrial
             fibrillation and/or conduction abnormality, e.g. congenital long QT syndrome, high-
             grade/complete AV-blockage

          -  Acute coronary syndromes (including myocardial infarction, unstable angina, coronary
             artery bypass graft [CABG], coronary angioplasty, or stenting), < 3 months prior to
             screening

          -  QT interval adjusted according to Fredericia (QTcF) > 480 msec on screening ECG

          -  Patients with diabetes mellitus requiring insulin treatment or uncontrolled
             steroid-induced diabetes mellitus.

          -  Any other condition that would, in the Investigator's judgment, preclude patient's
             participation in the clinical study due to safety concerns or compliance with clinical
             study procedures, e.g. infection/inflammation, intestinal obstruction,
             social/psychological complications.

          -  Impaired GI function or GI disease that may significantly alter the absorption of oral
             alpelisib (e.g. Uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or
             significant small bowel resection).

          -  Patients who are currently receiving medication with a known risk of prolonging the QT
             interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be
             discontinued or switched to a different medication prior to starting study drug
             treatment. A list of prohibited drugs with a known risk of TdP is provided in
             Appendix.

          -  Patient is currently receiving treatment with drugs known to be strong inhibitors or
             inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at
             least one week and must have discontinued strong inhibitors before the start of
             treatment. Switching to a different medication is allowed. (Refer to Appendix)

          -  Known positive serology for human immunodeficiency virus (HIV) (baseline testing not
             required)

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG laboratory test (> 5 mIU/mL)

          -  Patient who does not apply highly effective contraception during the study and through
             the duration as defined below after the final dose of study treatment:

        Sexually active males should use a condom during intercourse while taking drug and for 16
        weeks after the final dose of study treatment and should not father a child in this period,
        but may be recommended to seek advice on conservation of sperm. A condom is required to be
        used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

        Women of child-bearing potential, defined as all women physiologically capable of becoming
        pregnant, must use highly effective contraception during the study and through at least 16
        weeks after the final dose of study treatment. Highly effective contraception is defined as
        either:

        Total abstinence: When this is in line with the preferred and usual lifestyle of the
        subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation
        methods) and withdrawal are not acceptable methods of contraception].

        Female sterilization: have had surgical bilateral oophorectomy (with or without
        hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case
        of oophorectomy alone, only when the reproductive status of the woman has been confirmed by
        follow up hormone level assessment.

        Male partner sterilization (with the appropriate post-vasectomy documentation of the
        absence of sperm in the ejaculate). [For female study subjects, the vasectomized male
        partner should be the sole partner for that patient].

        Use a combination of the following (both a+b):

        Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of
        contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
        foam/gel/film/cream/vaginal suppository.

        Note: Hormonal contraception methods (e.g. oral, injected, and implanted) are not allowed
        Women are considered post-menopausal and not of child-bearing potential if they have had 12
        months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
        appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy
        (with or without hysterectomy) at least six weeks ago.

        For women with therapy-induced amenorrhea, oophorectomy or serial measurements of FSH
        and/or estradiol are needed to ensure postmenopausal status.

        NOTE: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH)
        agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian
        suppression.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximally tolerated dose of alpelisib in combination with cisplatin, based upon evaluation of dose-limiting toxicities and adverse events
Time Frame:Up to 21 days
Safety Issue:
Description:Measured using CTCAE v.4.03

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:Up to 30 days after the last administration of the study treatment
Safety Issue:
Description:RECIST v.1.1
Measure:Median duration of response
Time Frame:Up to 30 days after the last administration of the study treatment
Safety Issue:
Description:RECIST v.1.1
Measure:Median Progression-Free Survival
Time Frame:Up to 30 days after the last administration of the study treatment
Safety Issue:
Description:RECIST v.1.1
Measure:Incidence of adverse events of the treatment combination
Time Frame:Up to 30 days after the last administration of the study treatment
Safety Issue:
Description:CTCAE v.4.03

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pamela Munster

Trial Keywords

  • CDKN2A-p16 Positive
  • Locally Advanced Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm

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