Clinical Trials /

Dose-escalating AZD1775 + Concurrent Radiation + Cisplatin for Intermediate/High Risk HNSCC

NCT02585973

Description:

This open label, single-arm, Phase 1b study is designed to identify the maximum tolerated dose (MTD) using a traditional 3+3 dose escalation design of the WEE-1 inhibitor AZD1775 when added to standard of care chemotherapy (cisplatin) and radiation for the treatment of locally advanced squamous cell cancer of the head and neck (HNSCC).

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dose-escalating AZD1775 + Concurrent Radiation + Cisplatin for Intermediate/High Risk HNSCC
  • Official Title: Phase Ib Trial of Dose-escalating AZD1775 in Combination With Concurrent Radiation and Cisplatin for Intermediate and High Risk Head and Neck Squamous Cell Carcinoma (HNSCC)

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1430
  • NCT ID: NCT02585973

Conditions

  • Carcinoma, Squamous Cell of Head and Neck

Interventions

DrugSynonymsArms
AZD1775MK-1775 hemihydrate, L001739996-008Uopen label, single-arm, Phase 1b
Cisplatincisplatin injectionopen label, single-arm, Phase 1b

Purpose

This open label, single-arm, Phase 1b study is designed to identify the maximum tolerated dose (MTD) using a traditional 3+3 dose escalation design of the WEE-1 inhibitor AZD1775 when added to standard of care chemotherapy (cisplatin) and radiation for the treatment of locally advanced squamous cell cancer of the head and neck (HNSCC).

Detailed Description

      This open label, single-arm, Phase 1b study is designed to identify the maximum tolerated
      dose (MTD) using a traditional 3+3 dose escalation design of the WEE-1 inhibitor AZD1775
      when added to standard of care chemotherapy (cisplatin) and radiation for the treatment of
      locally advanced squamous cell cancer of the head and neck (HNSCC). The first cohort will
      include a starting dose of 50 mg AZD1775 given twice daily (BID) for three consecutive days
      (M-W) concomitantly with standard of care cisplatin and radiation. AZD1775 doses will be
      escalated in 50 mg increments up to 200 mg BID (M-W) in subsequent cohorts to determine the
      MTD.

      Up to 24 patients will be enrolled, depending on the rate of dose limiting toxicity (DLT).
      The investigators plan to characterize the toxicity (and safety) profile of this regimen.
      Secondary objectives include determination of the recommended phase 2 dose (RP2D; based on
      safety and other data considerations), objective response rate (ORR) at 12 weeks and
      progression free survival (PFS). the investigators will also estimate overall survival (OS)
      if the effective sample size allows. The investigators hypothesize that the investigators'
      proposed regimen is safe, and will yield an improved ORR and PFS over historical controls.
      Correlative studies will be performed on archival tissue, and on optional fresh biopsies
      performed at baseline and mid-treatment. The investigators will explore associations between
      p53 mutational status at baseline as well as changes in checkpoint markers, with ORR, PFS
      and OS. Finally, the investigators plan to describe possible changes in QOL, speech and
      swallowing.
    

Trial Arms

NameTypeDescriptionInterventions
open label, single-arm, Phase 1bOtherAZD1775 when added to standard of care concomitant chemotherapy (cisplatin) and radiation
  • AZD1775
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

        4.1.1 Age ≥ 18 years of age 4.1.2 ECOG Performance Status ≤ 2 (see section 12.4, Appendix
        D) 4.1.3 Biopsy proven HNSCC of the oropharynx, larynx, hypopharynx, or oral cavity Stage
        III-IVB as defined by American Joint Committee on Cancer (AJCC) T1- T4, N0 - N3, M0 4.1.4
        Must be considered Intermediate or High Risk Oropharynx Intermediate risk patients include
        those who have all of the following:

          -  HPV/p16 (+) disease, a significant tobacco smoking history (>10 pack years) and
             N2b-N3 disease OR

          -  HPV (-) disease, ≤ 10 years of smoking and large tumors (T2-T3) Oropharynx High risk
             patients include those who are either:

          -  HPV (-) with >10 years of smoking, OR

          -  HPV (-), ≤ 10 years of smoking and T4 disease Oral Cavity, Larynx, Hypopharynx are
             considered high/intermediate risk (regardless of HPV, p16 or smoking status) 4.1.5
             Required initial laboratory values:

          -  HgB ≥ 9.0 g/dL

          -  ANC≥1500/mm3

          -  Platelet count ≥ 100,000/mm3

          -  Serum creatinine ≤1.5 mg/dL and/or calculated creatinine clearance ≥50 mL/min(via
             Cockroft and Gault, see section 12.2, Appendix B)

          -  Bilirubin ≤ 1.25 x upper limits of normal (ULN)

          -  AST and ALT ≤ 2.0 x ULN 4.1.6 No prior definitive surgery for HNSCC 4.1.7
             Recommendation to undergo concurrent CRT, as determined by the treating physician,
             with a curative goal 4.1.8 Women of childbearing potential (WOCBP) should be willing
             to use 2 methods of birth control or be surgically sterile, or abstain from
             heterosexual activity for the course of the study. WOCBP are those who have not been
             surgically sterilized or have not been free from menses for > 1 year. The two birth
             control methods can be composed of: two barrier methods or a barrier method plus a
             hormonal method to prevent pregnancy. Subjects should start using birth control from
             the screening visit and continue throughout study mandated treatment and for 90 days
             after the final dose of study drug.

        The following are considered adequate barrier methods of contraception: diaphragm, condom
        (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal
        contraceptives will include any registered and marketed contraceptive agent that contains
        an estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or
        intramuscular agents).

        4.1.9 Male subjects should agree to use an adequate method of contraception starting with
        the first dose of study therapy and continuing through the last dose of study therapy and
        for 90 days after the final dose of study drug 4.1.10 Women of childbearing potential
        (WOCBP) must have negative pregnancy test within 72 hours prior to D1 of treatment 4.1.11
        Ability to swallow oral medications 4.1.12 As determined by the enrolling physician or
        protocol designee, ability of the patient to understand and comply with study procedures
        for the entire length of the study 4.1.13 Informed consent reviewed and signed

        Exclusion Criteria:

        4.2.1 Major surgical procedures ≤28 days prior to D1 of AZD1775 or minor surgical
        procedures ≤7 days; no waiting required following port-a-cath placement 4.2.2 Patients who
        have received prior radiation therapy for HNSCC 4.2.3 Myocardial infarction within 6
        months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart
        failure (see section 12.3, Appendix C), uncontrolled angina, severe uncontrolled
        ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active
        conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening
        has to be documented by the investigator as not medically relevant.

        • ECG ≤480 msec required on screening ECG 4.2.4 Not deemed a candidate for concurrent CRT
        for medical reasons, such as uncontrolled infection (including HIV), or uncontrolled
        diabetes mellitus which in the opinion of the treating physician, would make this protocol
        unreasonably hazardous for the patient.

        4.2.5 Not willing to avoid grapefruit, grapefruit juices, grapefruit hybrids, Seville
        oranges, pummelos, and exotic citrus fruits from 14 days prior to the dose of study
        medication, throughout the study, and until 2 weeks after the last dose of AZD1775 due to
        potential CYP3A4 interaction with the study medication. Orange juice is allowed.

        4.2.6 Patient has had prescription or non-prescription drugs or other products (ie,
        grapefruit juice) known to be moderate to strong inhibitors or inducers of CYP3A4, which
        cannot be discontinued 14 days before Day 1 of dosing and withheld throughout the study
        until 14 days after the last dose of AZD1775 (see section 12.5 Appendix E).
        Co-administration of aprepitant and fosaprepitant during this study is prohibited.
        Co-treatment with weak inhibitors of CYP3A4 is allowed.

        4.2.7 AZD1775 is an inhibitor of breast cancer resistance protein (BCRP). The use of
        statins including atorvastatin which are substrates for BCRP are therefore prohibited and
        patients should be moved on to non-BCRP alternatives.

        4.2.8 Unable or unwilling to discontinue use of any sensitive CYP3A4 substrates and CYP3A4
        substrates with a narrow therapeutic window (see section 12.5, Appendix E) 4.2.9
        Impairment of gastrointestinal (GI) function or GI disease that may significantly alter
        the absorption of AZD1775 (e.g., ulcerative diseases, uncontrolled nausea, vomiting,
        diarrhea, malabsorption syndrome, or small bowel resection) 4.2.10 Receiving or less than
        21 days since receiving any other concurrent cytotoxic, biologic agent(s) or
        investigational agent 4.2.11 Patients with a "currently active" second malignancy other
        than non-melanoma skin cancers, non-invasive bladder cancer, "low risk" adenocarcinoma of
        the prostate and carcinoma in situ of the cervix. Patients are not considered to have a
        "currently active" malignancy if they have completed therapy and are free of disease for ≥
        2 years.

        4.2.12 Pregnant or nursing
      
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:7 weeks
Safety Issue:
Description:Estimate maximum tolerated dose of AZD1775 in combination with cisplatin plus radiotherapy

Secondary Outcome Measures

Measure:Toxicity profile (Number of patients with adverse events)
Time Frame:7 weeks
Safety Issue:
Description:Number of patients with adverse events
Measure:Objective Response Rate
Time Frame:12 weeks
Safety Issue:
Description:Objective Response Rate = partial response (PR) + complete response (CR)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

Trial Keywords

  • AZD1775
  • Cisplatin
  • Head and Neck Squamous Cell Carcinoma
  • HNSCC
  • Chemoradiotherapy
  • Radiotherapy
  • CRT

Last Updated

July 1, 2016