Solid TumorsPhase 1NCT01748825
AZD1775 for Advanced Solid Tumors
A Phase 1 study testing MK-1775 (AZD1775) in people with Solid Tumors, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Solid Tumors
- What is being tested?
- MK-1775 (AZD1775)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 67 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Dec 2012to 19 May 2020
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Both men and women of all races and ethnic groups are eligible for this trial.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors
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.
Read more
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.
Read the 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.
- Conditions
- Solid Tumors
- Being tested
- MK-1775 (AZD1775)
- Keywords
- AZD1775, Adavosertib, MK-1775, Refractory, Solid Tumors, Wee1 Inhibitor, Tyrosine Kinase
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MK-1775 (AZD1775)Drug
Also called Adavosertib
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.
| Study group | Role | What they receive |
|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 2 AZD1775 225 mg Once Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 3 AZD1775 225 mg Twice Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing) | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 5 AZD1775 250 mg Once Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 6 AZD1775 300 mg Once Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 7 AZD1775 300 mg Twice Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 8 AZD1775 400 mg Once Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Experimental | Not described Receives: Drug: MK-1775 (AZD1775) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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 outcomes (1)
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.
Measured: 21 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Dec 2012 (estimated)
- Study start19 Dec 2012
- Primary completion19 May 2020
- Study completion19 May 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Solid TumorsStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 67 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Naoko Takebe, M.D., National Cancer Institute (NCI)
- Investigators
- Naoko Takebe, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01748825
- Sponsor's protocol ID
- 130032
- Other IDs
- 13-C-0032
- Status last verified
- Jun 2021
- First submitted
- 11 Dec 2012
- Last updated
- 26 Jul 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995 May 1;14(9):1878-91. doi: 10.1002/j.1460-2075.1995.tb07180.x.
PubMed 7743995Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2010 Jan 15;16(2):376-83. doi: 10.1158/1078-0432.CCR-09-1029. Epub 2010 Jan 12.
PubMed 20068082Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol. 2006 Jan;8(1):37-45. doi: 10.1038/ncb1337. Epub 2005 Dec 4.
PubMed 16327781Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, Kummar S. Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3409-15. doi: 10.1200/JCO.2014.60.4009. Epub 2015 May 11.
PubMed 25964244
Study at a glance
From the registry record, last updated by the sponsor on 26 Jul 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of Single-agent AZD1775 (MK-1775), a Wee1 Inhibitor, in Patients With Advanced Refractory Solid Tumors
- ClinicalTrials.gov ID
- NCT01748825
- Acronym / sponsor ID
- 130032
- Conditions
- Solid Tumors
- Keywords
- AZD1775, Adavosertib, MK-1775, Refractory, Solid Tumors, Wee1 Inhibitor, Tyrosine Kinase
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 67 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 19 Dec 2012 (actual)
- Primary completion
- 19 May 2020 (actual)
- Study completion
- 19 May 2020 (actual)
- First posted
- 13 Dec 2012 (estimated)
- Results
- Posted 26 Jul 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 10
| Arm | Type | Receives |
|---|---|---|
| ARM 1 AZD1775 200 mg Once Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 2 AZD1775 225 mg Once Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 3 AZD1775 225 mg Twice Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing) | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 5 AZD1775 250 mg Once Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 6 AZD1775 300 mg Once Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 7 AZD1775 300 mg Twice Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 8 AZD1775 400 mg Once Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily | Experimental | Drug: MK-1775 (AZD1775) |
| ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily | Experimental | Drug: MK-1775 (AZD1775) |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Both men and women of all races and ethnic groups are eligible for this trial.
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MK-1775 (AZD1775)Also: AdavosertibMK-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. | Drug | ARM 1 AZD1775 200 mg Once Daily, ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily, ARM 2 AZD1775 225 mg Once Daily, ARM 3 AZD1775 225 mg Twice Daily, ARM 4 AZD1775 225 mg Twice Daily (week 1-only dosing), ARM 5 AZD1775 250 mg Once Daily, ARM 6 AZD1775 300 mg Once Daily, ARM 7 AZD1775 300 mg Twice Daily, ARM 8 AZD1775 400 mg Once Daily, ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily |
Primary outcome
To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors
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.
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
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.
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.
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)
Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration.
1 secondary outcome
To Evaluate the Antitumor Activity of AZD1775 in Patients With Refractory Solid Tumors
Time frame: 21 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Jul 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 7743995Watanabe N, Broome M, Hunter T. Regulation of the human WEE1Hu CDK tyrosine 15-kinase during the cell cycle. EMBO J. 1995 May 1;14(9):1878-91. doi: 10.1002/j.1460-2075.1995.tb07180.x.
- Background: PubMed 20068082Dai Y, Grant S. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res. 2010 Jan 15;16(2):376-83. doi: 10.1158/1078-0432.CCR-09-1029. Epub 2010 Jan 12.
- Background: PubMed 16327781Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol. 2006 Jan;8(1):37-45. doi: 10.1038/ncb1337. Epub 2005 Dec 4.
- Derived from this study: PubMed 25964244Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH, Kummar S. Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 Kinase Inhibitor, in Patients With Refractory Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3409-15. doi: 10.1200/JCO.2014.60.4009. Epub 2015 May 11.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Naoko Takebe, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing MK-1775 (AZD1775) in people with Solid Tumors, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Jul 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Jul 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors (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.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01748825, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jul 2021; AzTrials last refreshed its copy on 3 Nov 2026.