Solid Tumors
Conditions
Keywords
AZD1775, Adavosertib, MK-1775, Refractory, Solid Tumors, Wee1 Inhibitor, Tyrosine Kinase
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 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
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.
Interventions
DRUGMK-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 tumor protein p53 (p53) signaling.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion 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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 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. | 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. |
| Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 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. | 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. |
| To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | 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) | Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | 21 days | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Dose-Limiting Toxicity (DLT) | First cycle (21 days) of treatment | DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of MK-1775 (Adavosertib (AZD1775). Examples are Grade ≥ 3 non-hematological toxicity, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding, Grade 3 fatigue of greater than 1 week duration, and failure to tolerate 100% of the dosing in the first cycle will be considered a DLT, etc. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ARM 1 AZD1775 200 mg Once Daily Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily | 6 |
| ARM 2 AZD1775 225 mg Once Daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily | 4 |
| ARM 3 AZD1775 225 mg Twice Daily Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily | 6 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing) | 3 |
| ARM 5 AZD1775 250 mg Once Daily Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily | 3 |
| ARM 6 AZD1775 300 mg Once Daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily | 6 |
| ARM 7 AZD1775 300 mg Twice Daily Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily | 3 |
| ARM 8 AZD1775 400 mg Once Daily Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily | 3 |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily | 13 |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily | 20 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Dose Escalation | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Dose Escalation | Refused further treatment | 2 | 2 | 0 | 0 | 1 | 2 | 0 | 0 | 0 | 0 |
| Dose Escalation | Switched to alternative treatment | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Dose Expansion | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 |
| Dose Expansion | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Dose Expansion | Refused further treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Dose Expansion | Switched to alternative treatment | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | ARM 8 AZD1775 400 mg Once Daily | ARM 7 AZD1775 300 mg Twice Daily | ARM 1 AZD1775 200 mg Once Daily | ARM 6 AZD1775 300 mg Once Daily | ARM 5 AZD1775 250 mg Once Daily | ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | ARM 3 AZD1775 225 mg Twice Daily | ARM 2 AZD1775 225 mg Once Daily |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 12 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 44 Participants | 8 Participants | 12 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 5 Participants | 2 Participants |
| Age, Continuous | 58 years STANDARD_DEVIATION 14.38 | 65.59 years STANDARD_DEVIATION 8.57 | 51.49 years STANDARD_DEVIATION 10.82 | 63.13 years STANDARD_DEVIATION 14.74 | 65.07 years STANDARD_DEVIATION 10.51 | 58.17 years STANDARD_DEVIATION 19 | 56.97 years STANDARD_DEVIATION 15.39 | 58.33 years STANDARD_DEVIATION 4.1 | 48.4 years STANDARD_DEVIATION 20.88 | 46.18 years STANDARD_DEVIATION 19.26 | 58.13 years STANDARD_DEVIATION 21.56 |
| Eastern Cooperative Oncology Score (ECOG) 0 | 7 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants |
| Eastern Cooperative Oncology Score (ECOG) 1 | 60 Participants | 17 Participants | 13 Participants | 3 Participants | 3 Participants | 5 Participants | 6 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 19 Participants | 12 Participants | 3 Participants | 3 Participants | 5 Participants | 6 Participants | 3 Participants | 3 Participants | 6 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Median Number of Prior Therapies | 7 prior therapy | 8 prior therapy | 7 prior therapy | 15 prior therapy | 2 prior therapy | 5 prior therapy | 3 prior therapy | 4 prior therapy | 11 prior therapy | 7.5 prior therapy | 3.5 prior therapy |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 54 Participants | 15 Participants | 12 Participants | 3 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment United States | 67 participants | 20 participants | 13 participants | 3 participants | 3 participants | 6 participants | 6 participants | 3 participants | 3 participants | 6 participants | 4 participants |
| Sex: Female, Male Female | 44 Participants | 16 Participants | 12 Participants | 2 Participants | 1 Participants | 3 Participants | 4 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 23 Participants | 4 Participants | 1 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 2 Participants | 0 Participants | 5 Participants | 3 Participants |
| Tumor Type Alveolar soft part sarcoma | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Appendiceal carcinoma | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Atypical granular cell paraspinal | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Bladder carcinoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tumor Type Breast carcinoma | 8 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tumor Type Cervical carcinoma | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Cholangiocarcinoma | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Colon adenocarcinoma | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Embryonal cell | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Endometrial carcinoma | 3 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Endometrial carcinosarcoma | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Ewing sarcoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Fallopian tube carcinoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Hepatocellular carcinoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Leiomyosarcoma | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Liposarcoma | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Malignant fibrous histiocytoma sarcoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Mesothelioma | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Tumor Type Non-small cell lung cancer | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tumor Type Ovarian carcinoma | 14 Participants | 6 Participants | 4 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Pancreatic carcinoma | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Papillary serous ovarian carcinoma | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Peritoneal carcinoma | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Pleomorphic sarcoma | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Prostate carcinoma | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Salivary adenocarcinoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Sinonasal leiomyosarcoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Squamous cell carcinoma | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Synovial cell carcinoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Tumor Type Synovial cell sarcoma | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Tumor Type Uterine carcinosarcoma | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 0 / 4 | 0 / 6 | 1 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 13 | 3 / 20 |
| other Total, other adverse events | 6 / 6 | 4 / 4 | 6 / 6 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 13 / 13 | 20 / 20 |
| serious Total, serious adverse events | 2 / 6 | 2 / 4 | 3 / 6 | 2 / 3 | 0 / 3 | 3 / 6 | 2 / 3 | 3 / 3 | 5 / 13 | 16 / 20 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 50 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 33 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 50 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 50 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 17 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 17 percentage of participants |
| ARM 1 AZD1775 200 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 17 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 25 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 0 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 75 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 75 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 25 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 25 percentage of participants |
| ARM 2 AZD1775 225 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 25 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 17 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 0 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 0 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 17 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 17 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 67 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 3 AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 50 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 0 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 33 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 67 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 33 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 67 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 0 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 33 percentage of participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 67 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 0 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 0 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 0 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 33 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 33 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 33 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 5 AZD1775 250 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 33 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 17 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 0 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 67 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 17 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 67 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 33 percentage of participants |
| ARM 6 AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 0 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 33 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 33 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 67 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 67 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 33 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 33 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 33 percentage of participants |
| ARM 7 AZD1775 300 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 33 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 100 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 67 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 67 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 67 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 33 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 100 percentage of participants |
| ARM 8 AZD1775 400 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 67 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 8 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 8 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 23 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 54 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 69 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 15 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 0 percentage of participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 0 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Lymphopenia | 25 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Lymphopenia | 10 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Neutropenia | 30 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 4 Neutropenia | 20 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Neutropenia | 25 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Lymphopenia | 80 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 3 Anemia | 30 percentage of participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | Grade 1-2 Anemia | 60 percentage of participants |
Primary
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.
Time frame: 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)
Population: Participants are grouped by dose level. Arm 3 represents combined data for patients receiving 225 mg twice daily on days 1-2 and once on day 3 of each 21-day cycle and for patients receiving 225 mg twice daily on days 1-2 and 8-9 and once on days 3 and 10 (the latter includes both dose escalation and expansion phase patients); these data are combined because all of these patients received the same dose over the pharmacokinetic analysis period (cycle 1 days 1-3).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | 597 nM | Standard Error 79 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | 782 nM | Standard Error 83 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | NA nM | — |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 135 nM | Standard Error 230 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | NA nM | — |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | NA nM | — |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 402 nM | Standard Error 327 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | 952 nM | Standard Error 66 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | NA nM | — |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | 790 nM | Standard Error 95 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | 235 nM | Standard Error 55 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 600 nM | Standard Error 18 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | NA nM | — |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | NA nM | — |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 579 nM | Standard Error 152 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | 461 nM | Standard Error 108 |
| ARM 1 AZD1775 200 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 416 nM | Standard Error 153 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | 985 nM | Standard Error 441 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 521 nM | Standard Error 232 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | 892 nM | Standard Error 367 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 577 nM | Standard Error 248 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 677 nM | Standard Error 351 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | NA nM | — |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 876 nM | Standard Error 420 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | NA nM | — |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | 961 nM | Standard Error 492 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | NA nM | — |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | 1128 nM | Standard Error 465 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | NA nM | — |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | NA nM | — |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | 1115 nM | Standard Error 440 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | NA nM | — |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 1017 nM | Standard Error 442 |
| ARM 2 AZD1775 225 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | 325 nM | Standard Error 231 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | NA nM | — |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | NA nM | — |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | NA nM | — |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | NA nM | — |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 592 nM | Standard Error 354 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | NA nM | — |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 661 nM | Standard Error 212 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 556 nM | Standard Error 210 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 422 nM | Standard Error 180 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | 776 nM | Standard Error 341 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | 983 nM | Standard Error 522 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | 1350 nM | Standard Error 673 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | 1440 nM | Standard Error 655 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 262 nM | Standard Error 257 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | 1210 nM | Standard Error 633 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | 1030 nM | Standard Error 509 |
| ARM 3 AZD1775 225 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | NA nM | — |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 462 nM | Standard Error 23 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | NA nM | — |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | NA nM | — |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 636 nM | Standard Error 43 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 539 nM | Standard Error 236 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | 1135 nM | Standard Error 266 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | 605 nM | Standard Error 147 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | 734 nM | Standard Error 88 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | 167 nM | Standard Error 48 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | NA nM | — |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | NA nM | — |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | 1114 nM | Standard Error 238 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | 787 nM | Standard Error 177 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | NA nM | — |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 276 nM | Standard Error 101 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 766 nM | Standard Error 36 |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | 1697 nM | Standard Error 1062 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 604 nM | Standard Error 373 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | 1638 nM | Standard Error 860 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 744 nM | Standard Error 412 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 979 nM | Standard Error 491 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 997 nM | Standard Error 703 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | 237 nM | Standard Error 82 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | 774 nM | Standard Error 394 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | NA nM | — |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | 965 nM | Standard Error 388 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | 1222 nM | Standard Error 491 |
| ARM 5 AZD1775 250 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 426 nM | Standard Error 377 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | NA nM | — |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 452 nM | Standard Error 402 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 878 nM | Standard Error 263 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 975 nM | Standard Error 361 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 780 nM | Standard Error 222 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 586 nM | Standard Error 209 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | 1560 nM | Standard Error 414 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | 2090 nM | Standard Error 403 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | 2440 nM | Standard Error 571 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | 2450 nM | Standard Error 583 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | 2190 nM | Standard Error 437 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | 1980 nM | Standard Error 455 |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | NA nM | — |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | NA nM | — |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | NA nM | — |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | NA nM | — |
| ARM 6 AZD1775 300 mg Once Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, pre-dose | 671 nM | Standard Error 156 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 8 hours post-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 6 hours post-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 4 hours post-dose | 2597 nM | Standard Error 211 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 4 hours post-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 2 hours post-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, 1 hour post-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 3, pre-dose | NA nM | — |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 8 hours post-dose | 1063 nM | Standard Error 256 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 8 hours post-dose | 1697 nM | Standard Error 115 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 6 hours post-dose | 2062 nM | Standard Error 511 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 6 hours post-dose | 1537 nM | Standard Error 469 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 4 hours post-dose | 1757 nM | Standard Error 351 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 2 hours post-dose | 1407 nM | Standard Error 314 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 1, 1 hour post-dose | 641 nM | Standard Error 452 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Pre-Treatment (Baseline) | 0 nM | Standard Error 0 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 2 hours post-dose | 3036 nM | Standard Error 572 |
| ARM 7 AZD1775 300 mg Twice Daily | To Determine the Pharmacokinetics of AZD1775 in Patients With Refractory Solid Tumors. | Cycle 1 Day 5, 1 hour post-dose | 1970 nM | Standard Error 301 |
Primary
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 6 Participants |
| ARM 2 AZD1775 225 mg Once Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 4 Participants |
| ARM 3 AZD1775 225 mg Twice Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 6 Participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 3 Participants |
| ARM 5 AZD1775 250 mg Once Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 3 Participants |
| ARM 6 AZD1775 300 mg Once Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 6 Participants |
| ARM 7 AZD1775 300 mg Twice Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 3 Participants |
| ARM 8 AZD1775 400 mg Once Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 3 Participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 13 Participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors | 20 Participants |
Secondary
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.
Time frame: 21 days
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 1 AZD1775 200 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 0 Participants |
| ARM 2 AZD1775 225 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 0 Participants |
| ARM 2 AZD1775 225 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 3 AZD1775 225 mg Twice Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 3 AZD1775 225 mg Twice Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 1 Participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 0 Participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 5 AZD1775 250 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 0 Participants |
| ARM 5 AZD1775 250 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 6 AZD1775 300 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 0 Participants |
| ARM 6 AZD1775 300 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 7 AZD1775 300 mg Twice Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 0 Participants |
| ARM 7 AZD1775 300 mg Twice Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 8 AZD1775 400 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 8 AZD1775 400 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 2 Participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 1 Participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Complete Response | 0 Participants |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors | Partial Response | 4 Participants |
Other Pre-specified
Number of Participants With a Dose-Limiting Toxicity (DLT)
DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of MK-1775 (Adavosertib (AZD1775). Examples are Grade ≥ 3 non-hematological toxicity, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding, Grade 3 fatigue of greater than 1 week duration, and failure to tolerate 100% of the dosing in the first cycle will be considered a DLT, etc.
Time frame: First cycle (21 days) of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |
| ARM 2 AZD1775 225 mg Once Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |
| ARM 3 AZD1775 225 mg Twice Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |
| ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing) | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |
| ARM 5 AZD1775 250 mg Once Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |
| ARM 6 AZD1775 300 mg Once Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |
| ARM 7 AZD1775 300 mg Twice Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 2 Participants |
| ARM 8 AZD1775 400 mg Once Daily | Number of Participants With a Dose-Limiting Toxicity (DLT) | 0 Participants |