Clinical Trials /

AZD1775 for Advanced Solid Tumors

NCT01748825

Description:

BACKGROUND: - Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to DNA damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase. - AZD1775 is a selective inhibitor of Wee1 kinase. Recent preclinical model data additionally show single agent anti-tumor activity in multiple cancer cell lines and tumor xenografts. - Preliminary data show AZD1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775. PRIMARY OBJECTIVE: - To establish the safety and tolerability of single-agent AZD1775 in patients with refractory solid tumors - To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors SECONDARY OBJECTIVES: - To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells - To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors EXPLORATORY OBJECTIVES: -To identify tumor genomic alterations and gene expression patterns potentially associated withAZD1775 antitumor activity ELIGIBILITY: - Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival have failed, or for which standard therapies do not exist. - No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever is shorter) prior to entering the study. - Adequate organ function STUDY DESIGN: - This study will follow a traditional 3+3 design. - In Arm A starting at dose level 1, AZD1775 will be administered orally, BID, for 5 doses (D1-3) during each cycle. Starting at dose level 2 and onwards, AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling). - Once MTD is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for PK and PD endpoints. - A further expansion arm of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will also be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population. - Based on preliminary evidence of drug activity in an alternative once-daily dosing schedule, patients without a documented BRCA mutation will be accrued to a once-daily dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1 day for scheduling). - During the escalation phase, tumor biopsies will be optional and will be evaluated for pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and apoptosis (yH2AX, pNbs1, Rad51, pTyr15-Cdk and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD endpoints.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AZD1775 for Advanced Solid Tumors
  • Official Title: A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 130032
  • SECONDARY ID: 13-C-0032
  • NCT ID: NCT01748825

Conditions

  • Neoplasms
  • Lymphoma

Interventions

DrugSynonymsArms
MK-1775 (AZD1775)A

Purpose

BACKGROUND: - Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to DNA damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase. - AZD1775 is a selective inhibitor of Wee1 kinase. Recent preclinical model data additionally show single agent anti-tumor activity in multiple cancer cell lines and tumor xenografts. - Preliminary data show AZD1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775. PRIMARY OBJECTIVE: - To establish the safety and tolerability of single-agent AZD1775 in patients with refractory solid tumors - To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors SECONDARY OBJECTIVES: - To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells - To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors EXPLORATORY OBJECTIVES: -To identify tumor genomic alterations and gene expression patterns potentially associated withAZD1775 antitumor activity ELIGIBILITY: - Patients must have histologically confirmed solid tumors for which all standard therapy known to prolong survival have failed, or for which standard therapies do not exist. - No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever is shorter) prior to entering the study. - Adequate organ function STUDY DESIGN: - This study will follow a traditional 3+3 design. - In Arm A starting at dose level 1, AZD1775 will be administered orally, BID, for 5 doses (D1-3) during each cycle. Starting at dose level 2 and onwards, AZD1775 will be administered orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8- 10). Each cycle is 21 days (+/- 1 day for scheduling). - Once MTD is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for PK and PD endpoints. - A further expansion arm of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will also be enrolled at the MTD to further explore the safety of the agent and obtain preliminary evidence of activity in this patient population. - Based on preliminary evidence of drug activity in an alternative once-daily dosing schedule, patients without a documented BRCA mutation will be accrued to a once-daily dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1 day for scheduling). - During the escalation phase, tumor biopsies will be optional and will be evaluated for pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and apoptosis (yH2AX, pNbs1, Rad51, pTyr15-Cdk and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20 additional patients enrolled at the MTD to further evaluate PD endpoints.

Detailed Description

      BACKGROUND:

        -  Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of
           cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest
           in response to DNA damage to allow time for DNA repair. Recent preclinical data
           additionally implicates Wee1 in maintenance of genomic integrity during S phase.

        -  AZD1775 is a selective inhibitor of Wee1 kinase. Recent preclinical model data
           additionally show single agent anti-tumor activity in multiple cancer cell lines and
           tumor xenografts.

        -  Preliminary data show AZD1775 is tolerable at lower doses in combination with
           chemotherapeutic agents. We propose to demonstrate single-agent activity for AZD1775.

      PRIMARY OBJECTIVE:

        -  To establish the safety and tolerability of single-agent AZD1775 in patients with
           refractory solid tumors

        -  To determine the pharmacokinetics of AZD1775 in patients with refractory solid tumors

      SECONDARY OBJECTIVES:

      -To evaluate the antitumor activity of AZD1775 in patients with refractory solid tumors

      EXPLORATORY OBJECTIVES:

      -To determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor

      tissue and circulating tumor cells

        -  To assess whether sufficient Wee1 inhibition is maintained throughout the therapeutic
           regimen

        -  To identify tumor genomic alterations and gene expression patterns potentially
           associated withAZD1775 antitumor activity

      ELIGIBILITY:

        -  Patients must have histologically confirmed solid tumors for which all standard therapy
           known to prolong survival have failed, or for which standard therapies do not exist.

        -  No major surgery, radiation, or chemotherapy within 3 weeks or (5 half-lives, whichever
           is shorter) prior to entering the study.

        -  Adequate organ function

      STUDY DESIGN:

        -  This study will follow a traditional 3+3 design.

        -  In Arm A starting at dose level 1, AZD1775 will be administered orally, BID, for 5 doses
           (D1-3) during each cycle. Starting at dose level 2 and onwards, AZD1775 will be
           administered orally, BID, for 5 doses for the first 2 weeks of each cycle (D1-3 and 8-
           10). Each cycle is 21 days (+/- 1 day for scheduling).

        -  Once MTD is established, 6 additional patients will be enrolled at the MTD to further
           evaluate that dose for PK and PD endpoints.

        -  A further expansion arm of 6 additional patients with documented tumors harboring BRCA-1
           or -2 mutations will also be enrolled at the MTD to further explore the safety of the
           agent and obtain preliminary evidence of activity in this patient population.

        -  Based on preliminary evidence of drug activity in an alternative once-daily dosing
           schedule, patients without a documented BRCA mutation will be accrued to a once-daily
           dosing schedule Arm B, with mandatory paired tumor biopsies at the maximum tolerated
           single daily dose, to further evaluate PD endpoints. AZD1775 will be administered orally
           once daily for 5 days (D1-5 and 8-12) during weeks 1 and 2 of each 21-day cycle (+/- 1
           day for scheduling).

        -  During the escalation phase, tumor biopsies will be optional and will be evaluated for
           pharmacodynamic (PD) studies for evidence of Wee1 inhibition DNA damage and repair, and
           apoptosis (yH2AX, pNbs1, Rad51, pTyr15-Cdk and caspase 3). During the expansion phase,
           once MTD is reached, mandatory paired tumor biopsies will be pursued in up to 20
           additional patients enrolled at the MTD to further evaluate PD endpoints.
    

Trial Arms

NameTypeDescriptionInterventions
AExperimentalMK-1775 (AZD1775) administered orally for 5 doses each cycle, starting at 225 mg per dose approximately 12 hours apart
  • MK-1775 (AZD1775)
BExperimentalMK-1775 (AZD1775) administered orally for 5 doses for 2 weeks each cycle, starting at 200 mg per day
  • MK-1775 (AZD1775)

Eligibility Criteria

        -  ELIGIBILITY CRITERIA:

          -  Patients must have histologically confirmed solid tumors for which all standard
             therapy known to prolong survival have failed or for which standard therapies do not
             exist.

          -  Patients must have measurable disease or evaluable disease for the escalation phase;
             for the 6 additional patients enrolled at MTD for further evaluation of PK and PD
             endpoints (Expansion Cohort A). For the 6-patient BRCA-mutation expansion cohort,
             patients must have measurable disease; however, tumor biopsies are optional. For
             Expansion Cohort B, patients must have tumor amenable to biopsy (excisional or
             incision biopsies of skin or H & N lesions under visualization) and willingness to
             undergo a tumor biopsy or patient will be undergoing a procedure due to medical
             necessity during which the tissue may be collected, or tumor biopsy tissue from a
             previous research study or medical care is available for submission at registration.
             Criteria for the submission of tissue are:

               -  Tissue must have been collected within 3 months prior to registration

               -  Patient has not received any intervening therapy for their cancer since the
                  collection of the tumor sample

               -  Tumor tissue must meet the minimum requirements

          -  Patients must have completed any chemotherapy, radiation therapy, surgery, or biologic
             therapy greater than or equal to 3 weeks (or > 5 half-lives, whichever is shorter)
             prior to entering the study. Patients must be greater than or equal to 2 weeks since
             any prior administration of a study drug in an exploratory IND/Phase 0 study or more
             than or equal to 1 week from palliative radiation therapy. Patients must have
             recovered to eligibility levels from prior toxicity or adverse events.

          -  Age greater than or equal to 18 years of age.

          -  ECOG performance status less than or equal to 1 (Karnofsky >60%)

          -  Life expectancy of greater than 3 months.

          -  Patients must have normal organ and marrow function as defined below:

               -  leukocytes greater than or equal to 3,000/mcL

               -  absolute neutrophil count greater than or equal to 1,500/mcL

               -  platelets greater than or equal to 100,000/mcL

               -  hemoglobin >9 g/dL

               -  total bilirubin less than or equal to 1.5 times institutional upper limit of
                  normal

               -  AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
                  normal

               -  creatinine less than or equal to 1.5 times institutional upper limit of normal OR

               -  creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients
                  with creatinine levels above institutional normal.

          -  The effects of AZD1775 on the developing human fetus are unknown. For this reason and
             because molecular inhibitors of Wee1 kinase are known to be teratogenic, women of
             child-bearing potential (WoCBP) may be included only if acceptable contraception is in
             place for two weeks before study entry, for the duration of the treatment with the
             study drug, and for 2 months after the last dose of AZD1775. Male patients who are
             involved in the study must agree to avoid procreative and unprotected sex (i.e., by
             using acceptable forms of contraception) and must not donate sperm during the study
             and for 3 months after the last dose of AZD1775. Where the female partner is pregnant
             or not using effective birth control, men should be advised to abstain while in the
             study and for 3 months after the last dose of AZD1775. Female partners, who are of
             child-bearing potential, of men participating in clinical studies of AZD1775 will also
             be required to use effective contraceptive measures while their partner is on study
             drug and for 3 months thereafter. Male patients will be advised to arrange for the
             freezing of sperm samples prior to the start of the study should they wish to father
             children while on AZD1775 or during the 3 months after stopping AZD1775.

          -  Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with the study drugs, breastfeeding should be
             discontinued prior to the first of study drug and women should refrain from nursing
             throughout the treatment period and for 14 days following the last dose of study drug.

          -  Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube
             administration is not allowed. Any gastrointestinal disease which would impair ability
             to swallow, retain, or absorb drug is not allowed.

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

          -  Patients with prostate cancer can continue to receive treatment with GnRH agonists
             while on study, as long as there is evidence of disease progression on therapy.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Patients with known active brain metastases or carcinomatous meningitis are excluded
             from this clinical trial. Patients whose brain metastatic disease status has remained
             stable for greater than or equal to 4 weeks following treatment of brain metastases
             are eligible to participate at the discretion of the principal investigator.

          -  Eligibility of subjects receiving any medications or substances with the potential to
             affect the activity or pharmacokinetics of AZD1775 will be determined following review
             by the principal investigator.

          -  Patients receiving any medications or substances that are inhibitors or inducers of
             CYP3A4, or CYP3A4 substrates need to be reviewed by the principal investigator.
             Continuation of such medications will be at the discretion of the principal
             investigator. Concomitant use of aprepitant or fosaprepitant is prohibited. As
             grapefruit and Seville oranges are known to contain moderate inhibitors of CYP3A4,
             these fruits or their products (including marmalade, juice, etc.) should be avoided
             while taking AZD1775. The use of sensitive substrates of CYP3A4, such as atorvastatin,
             simvastatin and lovastatin, is also prohibited in this study. Herbal preparations are
             not allowed throughout the study. These herbal medications include but are not limited
             to: St. John's wort, kava, ephedra (mahung), gingko biloba, dehydroepiandrosterone
             (DHEA), yohimbe, saw palmetto and ginseng.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, 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 because the effects of the study drugs on
             the developing fetus are unknown.

          -  HIV positive patients on antiretroviral therapy are ineligible because of the
             potential for PK interactions.

        INCLUSION OF WOMEN AND MINORITIES:

        Both men and women of all races and ethnic groups are eligible for this trial.
      
Maximum Eligible Age:120 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and Tolerability
Time Frame:21 days
Safety Issue:
Description:safety and tolerability of AZD1775 in patients with advanced refractory solid tumors

Secondary Outcome Measures

Measure:evaluate the antitumor activity of MK-1775 (AZD1775) in patients with refractory solid tumors
Time Frame:60 days
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • MK-1775
  • Refractory
  • Solid Tumors
  • Wee1 Inhibitor
  • Tyrosine Kinase

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