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MK-1775 for Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01748825
First received: December 11, 2012
Last updated: September 3, 2014
Last verified: April 2014
  Purpose

BACKGROUND:

  • Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclindependent 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.
  • MK-1775 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 MK-1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for MK-1775.

PRIMARY OBJECTIVE:

  • To establish the safety and tolerability of single-agent MK-1775 in patients with refractory solid tumors
  • To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors

SECONDARY OBJECTIVES:

  • To determine the effect of MK-1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells
  • To evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors

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 4 weeks prior to entering the study
  • Adequate organ function

Study Design:

  • This study will follow a traditional 3+3 design.
  • In Cohort A starting at dose level 1, MK-1775 (AZD1775) will be administered orally, BID, for 5 doses (D1-3) during each cycle. Starting at dose level 2 and onwards, MK-1775 (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 cohort of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will lso 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 Cohort B, for up to two dose levels, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. MK-1775 (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 DNA damage, repair, and apoptosis (H2AX, pNbs1, ERCC1, and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in the 6 additional patients enrolled at the MTD to further evaluate PD endpoints.

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Condition Intervention Phase
Neoplasms
Lymphoma
Drug: MK-1775 (AZD1775)
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Single-agent MK-1775, a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Safety and Tolerability [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
  • Determine pharmacokinetics of MK-1775 (AZD1775) in patients with refractory solid tumors [ Time Frame: 21 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Determine the effect of MK-1775 (AZD1775) on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells [ Time Frame: 60 days ] [ Designated as safety issue: No ]
  • Evaluate the antitumor activity of MK-1775 (AZD1775) in patients with refractory solid tumors [ Time Frame: 60 days ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: November 2012
Estimated Study Completion Date: September 2015
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
MK-1775 (AZD1775) administered orally for 5 doses each cycle, starting at 225 mg per dose approximately 12 hours apart
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.
Experimental: B
MK-1775 (AZD1775) administered orally for 5 doses for 2 weeks each cycle, starting at 200 mg per day
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.

Detailed Description:

BACKGROUND:

  • Wee1 is a tyrosine kinase involved in the phosphorylation and inactivation of cyclindependent 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.
  • MK-1775 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 MK-1775 is tolerable at lower doses in combination with chemotherapeutic agents. We propose to demonstrate single-agent activity for MK-1775.

PRIMARY OBJECTIVE:

  • To establish the safety and tolerability of single-agent MK-1775 in patients with refractory solid tumors
  • To determine the pharmacokinetics of MK-1775 in patients with refractory solid tumors

SECONDARY OBJECTIVES:

  • To determine the effect of MK-1775 on markers of DNA damage and apoptosis in tumor tissue and circulating tumor cells
  • To evaluate the antitumor activity of MK-1775 in patients with refractory solid tumors

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 4 weeks prior to entering the study
  • Adequate organ function

Study Design:

  • This study will follow a traditional 3+3 design.
  • In Cohort A starting at dose level 1, MK-1775 (AZD1775) will be administered orally, BID, for 5 doses (D1-3) during each cycle. Starting at dose level 2 and onwards, MK-1775 (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 cohort of 6 additional patients with documented tumors harboring BRCA-1 or -2 mutations will lso 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 Cohort B, for up to two dose levels, with mandatory paired tumor biopsies at the maximum tolerated single daily dose, to further evaluate PD endpoints. MK-1775 (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 DNA damage, repair, and apoptosis (H2AX, pNbs1, ERCC1, and caspase 3). During the expansion phase, once MTD is reached, mandatory paired tumor biopsies will be pursued in the 6 additional patients enrolled at the MTD to further evaluate PD endpoints.

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  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 esclation phase; for the 6 additional patients enrolled at MTD for further evaluation of PK and PD endpoints, patients must have disease amenable to biopsy and be willing to undergo biopsy. For the 6-patient BRCA-mutation expansion cohort, patients must have measurable disease; however, tumor biopsies are optional.
  • Patients must have completed any chemotherapy, radiation therapy, surgery, or biologic therapy greater than or equal to 4 weeks 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. Patients must have recovered to eligibility levels from prior toxicity or adverse events.
  • Age greater than or equal to18 years of age.
  • ECOG performance status less than or equal to 2 (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
  • 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 MK-1775 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 and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 2 months after completion of MK-1775 administration.
  • 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.

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 MK-1775 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 is prohibited.
  • 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.< TAB>

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01748825

Contacts
Contact: Jennifer H Zlott (301) 435-5664 zlottjh@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01748825     History of Changes
Other Study ID Numbers: 130032, 13-C-0032
Study First Received: December 11, 2012
Last Updated: September 3, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
MK-1775
Refractory
Solid Tumors
Wee1 Inhibitor
Tyrosine Kinase

ClinicalTrials.gov processed this record on November 24, 2014