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AZD1775 for Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT01748825
Recruitment Status : Active, not recruiting
First Posted : December 13, 2012
Last Update Posted : January 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE December 11, 2012
First Posted Date  ICMJE December 13, 2012
Last Update Posted Date January 17, 2019
Actual Study Start Date  ICMJE December 19, 2012
Estimated Primary Completion Date August 5, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2017)
  • Safety and Tolerability [ Time Frame: 21 days ]
    safety and tolerability of AZD1775 in patients with advanced refractory solid tumors
  • Determine pharmacokinetics of AZD1775 in patients with refractory solid tumors [ Time Frame: 21 days ]
    Determine pharmacokinetics of AZD1775 in patients with advanced refractory solid tumors
Original Primary Outcome Measures  ICMJE
 (submitted: December 11, 2012)
  • To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors [ Time Frame: January, 2014 ]
  • To establish the safety and tolerability of single-agent MK-1775 in patients with refractory solid tumors. [ Time Frame: January, 2014 ]
Change History Complete list of historical versions of study NCT01748825 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2018)
evaluate the antitumor activity of MK-1775 (AZD1775) in patients with refractory solid tumors [ Time Frame: 60 days ]
Original Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2012)
  • Determine the effect of MK-1775 on MAKERS DNA damage and apoptosis [ Time Frame: January, 2014 ]
  • Evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors [ Time Frame: January, 2014 ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE AZD1775 for Advanced Solid Tumors
Official Title  ICMJE A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors
Brief Summary

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.
Study Type  ICMJE Interventional
Study Phase Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Neoplasms
  • Lymphoma
Intervention  ICMJE Drug: MK-1775 (AZD1775)
MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in p53 signaling.
Study Arms
  • Experimental: A
    MK-1775 (AZD1775) administered orally for 5 doses each cycle, starting at 225 mg per dose approximately 12 hours apart
    Intervention: Drug: MK-1775 (AZD1775)
  • Experimental: B
    MK-1775 (AZD1775) administered orally for 5 doses for 2 weeks each cycle, starting at 200 mg per day
    Intervention: Drug: MK-1775 (AZD1775)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 2, 2018)
66
Original Estimated Enrollment  ICMJE
 (submitted: December 11, 2012)
40
Estimated Study Completion Date September 27, 2020
Estimated Primary Completion Date August 5, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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.

Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01748825
Other Study ID Numbers  ICMJE 130032
13-C-0032
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Naoko Takebe, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date January 7, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP