Clinical Trials /

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:

Recruiting

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
  • NCT ID: NCT02620839

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
AlpelisibCohort 1A
CisplatinCohort 1A

Purpose

This is a Phase Ib dose escalation / expansion study with the combination of alpelisib and weekly cisplatin. Dose escalation will follow standard 3+3 design. During dose escalation, two dose levels of weekly cisplatin (30 and 35 mg/m2, respectively) will be evaluated in combination with escalating doses of alpelisib in parallel. Cohort B (cisplatin 35 mg/m2) at a given dose level of alpelisib to open only after corresponding A cohort (cisplatin 30 mg/m2) at the same dose level of alpelisib has cleared DLT window. Cohorts A and B may enroll in parallel (e.g., Cohort 3A may enroll in parallel with Cohort 2B) as shown below in the dose escalation schema. Intermediate dose levels and alternative dosing schedules may be investigated per the discretion of Principal Investigator using same 3+3 dose escalation schema (e.g. cisplatin administered days 1, 8 of 21 day cycle).

Detailed Description

      The starting dose of alpelisib at 200 mg once daily was chosen based upon the aggregate of
      safety, PK, and efficacy data shown above, indicating:

        1. Single agent activity of alpelisib at daily doses of 200 mg and above

        2. Largely non-overlapping toxicity profile between alpelisib and cisplatin

        3. MTD of alpelisib in combination with cetuximab in prior study was 300 mg once daily.

      The investigators will escalate at 50 mg increments per dose level, up to a maximum dose of
      350 mg daily. Though the single agent MTD/RP2D of alpelisib is 400 mg, in combination with a
      variety of targeted therapies the MTD/RP2D is in the range of 300-350 mg daily.

      The investigators chose a weekly cisplatin dosing schedule which has demonstrated activity
      in squamous cell carcinoma of the head and neck and cervix. Both 30 and 35 mg/m2 of
      cisplatin weekly have been shown to have activity in HNSCC and other squamous cell
      histologies, and the investigators will investigate both dose levels in combination with
      alpelisib as shown in section 3 of the protocol.
    

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 109/L

          -  Platelet count ≥ 100 x 109/L

          -  Hemoglobin ≥ 9.0 g/dL

          -  Serum creatinine < 1.5 x ULN OR Estimated GFR by Cockroft-Gault equation OR 24 hour
             urine collection ≥ 50 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

          -  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 documented
             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
        as alpelisib may decrease the effectiveness of hormonal contraceptives.

        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:Maximum Tolerated Dose
Time Frame:Up to 2 years
Safety Issue:
Description:CTCAE v.4.03

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:Up to 2 years
Safety Issue:
Description:RECIST v.1.1
Measure:Median Progression-Free Survival
Time Frame:Up to 2 years
Safety Issue:
Description:RECIST v.1.1
Measure:Toxicity
Time Frame:Up to 2 years
Safety Issue:
Description:CTCAE v.4.03
Measure:Alpelisib plasma concentration
Time Frame:Up to 2 years
Safety Issue:
Description:Measured using a validated liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay

Details

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

Trial Keywords

  • HPV+

Last Updated

May 2, 2017