AZD1775 for Advanced Solid Tumors

Study Overview
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Brief Summary
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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 deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase. Adavosertib (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 with AZD1775 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, twice a day (BID), for 5 doses (Day (D) 1-3) 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 maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics (PD) endpoints. A further expansion arm of 6 additional patients with documented tumors harboring breast cancer type 1 or 2 (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 (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1), Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (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
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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 deoxyribonucleic acid (DNA) damage to allow time for DNA repair. Recent preclinical data additionally implicates Wee1 in maintenance of genomic integrity during S phase. Adavosertib (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, twice a day (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 maximum tolerated dose (MTD) is established, 6 additional patients will be enrolled at the MTD to further evaluate that dose for pharmacokinetics (PK) and pharmacodynamics (PD) endpoints. A further expansion arm of 6 additional patients with documented tumors harboring breast cancer type 1 or 2 (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 (gamma H2A histone family member X (yH2AX), phosphorylated Nbs1 (pNbs1), Rad51, Rabbit polyclonal phospho-cyclin-dependent kinases (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.

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

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: MK-1775 (AZD1775)


Participation Criteria
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Eligibility Criteria
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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 maximum tolerated dose (MTD) for further evaluation of pharmacokinetics (PK) and pharmacodynamics (PD) endpoints (Expansion Cohort A). For the 6-patient breast cancer gene (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 head (H) & neck (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 Investigational New Drug (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. Eastern Cooperative Oncology Group (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 Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (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 Adavosertib (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 gonadotropin-releasing hormone (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 Cytochrome P450 3A4 (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. Human immunodeficiency virus (HIV) positive patients on antiretroviral therapy are ineligible because of the potential for pharmacokinetics (PK) interactions. INCLUSION OF WOMEN AND MINORITIES: Both men and women of all races and ethnic groups are eligible for this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM 1 AZD1775 200 mg Once Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 2 AZD1775 225 mg Once Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 3 AZD1775 225 mg Twice Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing)<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 5 AZD1775 250 mg Once Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 6 AZD1775 300 mg Once Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 7 AZD1775 300 mg Twice Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 8 AZD1775 400 mg Once Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|
| Experimental: ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily<br> | Drug: MK-1775 (AZD1775)<br>* MK-1775 (AZD1775) is an inhibitor of Wee1-kinase.In preclinical models, MK-1775 selectively enhanced chemotherapy-induced death of cells deficient in tumor protein p53 (p53) signaling.<br>* Other names: Adavosertib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10. | 
| Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant but not immediately life-threatening. Grade 4 is life-threatening. | Date treatment consent signed to date off study, approx.19 mo/8 d for A1, 3 mo/28 d for A2, 10 mo/28 d for A3, 2 mo/14 d for A4, 20 mo/24 d for A5, 10 mo/23 d for A6, 4 mo/23 d for A7, 14 mo/11 d for A8, 15 mo/24 d for A9, and 77 mo/6 d for A10. | 
| To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration. | Pre-Treatment (Baseline) and Cycle 1 Days 1 and 3 (Arms 3 and 7) or Days 1 and 5 (Arms 1-2, 5-6, and 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Objective Response is defined as a Complete Response + Partial Response and was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. | 21 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD1775, Adavosertib, MK-1775, Refractory, Solid Tumors, Wee1 Inhibitor, Tyrosine Kinase