Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Lung Neoplasms

Recurrence

Small Cell Lung Carcinoma

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Etoposide

Carboplatin

Etoposide phosphate

Enzyme Inhibitors

Participants will receive Debio 0123 escalating doses, orally along with etoposide IV infusion and carboplatin IV infusion in 21-day cycles until disease progression or death or end of study.

Participants will receive Debio 0123 recommended dose determined in Part 1 of the study, orally along with etoposide IV infusion and carboplatin IV infusion in 21-day cycles until disease progression or death or end of study.

Debio 0123

Debiopharm International S.A

The primary purpose of part 1 (dose escalation) of this study is to identify the recommended dose and to characterize the safety and tolerability of Debio 0123 in combination with carboplatin and etoposide.

The primary purpose of part 2 (dose expansion) of this study is to characterize the safety and tolerability of Debio 0123 at the recommended dose when administered in combination with carboplatin and etoposide.

Debio 0123 in Combination With Carboplatin and Etoposide in Adult Participants With Small Cell Lung Cancer That Recurred or Progressed After Previous Standard Platinum-Based Therapy

A Phase 1 Dose-Escalation and Expansion Study to Assess Safety and Preliminary Antitumor Activity of Debio 0123 in Combination With Carboplatin and Etoposide in Adult Participants With Small Cell Lung Cancer That Recurred or Progressed After Previous Standard Platinum-Based Therapy

Debiopharm International SA

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Participants will receive Debio 0123, escalating doses along with temozolomide (TMZ) in each 28-day cycle for up to 2 years.

Participants will receive Debio 0123, escalating doses along with TMZ and concomitant administration of radiotherapy (RT) for up to 6 weeks.

Participants will receive Debio 0123 RP2D along with TMZ in each 28-day cycle for up to 2 years.

Administered in accordance with the local clinical practice and applicable Radiation Therapy Oncology Group (RTOG) or the European Organization for Research and Treatment of Cancer (EORTC) guidelines.

Radiotherapy

Study Director

The primary purpose of Phase 1 (dose escalation) of this study is to identify the recommended Phase 2 dose (RP2D) of Debio 0123 in combination with temozolomide (TMZ) (Arm A) and in combination with TMZ and radiotherapy (RT) (Arm B) and to characterize the safety and tolerability of these combinations in adult participants with glioblastoma (GBM).

The primary purpose of Phase 2 of this study is to assess the efficacy of Debio 0123 at the RP2D in combination with TMZ, compared to standard of care (SOC) in adult participants with GBM.

Parallel assignment applies to the arm groups within Phase 1 of the study. Sequential assignment will apply to Phases 1 and 2 of the study.

A Study of Debio 0123 in Combination With Temozolomide in Adult Participants With Recurrent or Progressive Glioblastoma and of Debio 0123 in Combination With Temozolomide and Radiotherapy in Adult Participants With Newly Diagnosed Glioblastoma

A Phase 1/2 Open-label Study of Debio 0123 in Combination With Temozolomide in Adult Participants With Recurrent or Progressive Glioblastoma and of Debio 0123 in Combination With Temozolomide and Radiotherapy in Adult Participants With Newly Diagnosed Glioblastoma

KPS is an assessment tool for functional impairment. It is a standard way of measuring the ability of participants with cancer to perform ordinary tasks. The KPS scores range from 0 (death) to 100 (no evidence of disease). A higher score means the participant is better able to carry out daily activities.

The pharmacokinetics (PK) of Debio-0123 and its metabolite will be evaluated in plasma.

The PK of temozolomide will be evaluated in plasma.

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Irinotecan

Adavosertib

Topoisomerase I Inhibitors

Group AZD1775 (study drug); Irinotecan (chemotherapy)

1) 125 mg two times a day (BID) for 3 days every 2 weeks; 180mg/m2 every 2 weeks

2A) 150 mg BID for 3 days every 2 weeks; 180mg/m2 every 2 weeks

2B) 125 mg BID for 5 days every 2 weeks; 180mg/m2 every 2 weeks

3) 150 mg BID for 5 days every 2 weeks ; 180mg/m2 every 2 weeks

AZD1775

Deirdre Cohen, MD

The purpose of this study is to determine whether combination therapy of irinotecan with AZD1775 is safe and effective in treating mutated metastatic colorectal cancer patients.

Study of Irinotecan and AZD1775, a Selective Wee 1 Inhibitor, in RAS or BRAF Mutated, Second-line Metastatic Colorectal Cancer

A Phase Ib Study Combining Irinotecan With AZD1775, a Selective Wee 1 Inhibitor, in RAS (KRAS or NRAS) or BRAF Mutated Metastatic Colorectal Cancer Patients Who Have Progressed on First Line Therapy

AstraZeneca

NYU Langone Health

Amino Acids

Tyrosine

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.

MK-1775 (AZD1775)

Naoko Takebe, M.D.

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.

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.

AZD1775 for Advanced Solid Tumors

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

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.

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.

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.

Mean plasma concentration (± standard deviation) of AZD1775 at baseline and after AZD1775 administration.

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.

National Cancer Institute (NCI)

Principal Investigator

Cycle = 21 days. MK-1775 (AZD1775) 200 mg by mouth (PO) once daily

ARM 1 AZD1775 200 mg Once Daily

Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) once daily

ARM 2 AZD1775 225 mg Once Daily

Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily

ARM 3 AZD1775 225 mg Twice Daily

Cycle = 21 days. MK-1775 (AZD1775) 225 mg by mouth (PO) twice daily (week 1-only dosing)

ARM 4 AZD1775 225 mg Twice Daily (Week 1-only Dosing)

Cycle = 21 days. MK-1775 (AZD1775) 250 mg by mouth (PO) once daily

ARM 5 AZD1775 250 mg Once Daily

Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) twice daily

ARM 6 AZD1775 300 mg Once Daily

ARM 7 AZD1775 300 mg Twice Daily

Cycle = 21 days. MK-1775 (AZD1775) 400 mg by mouth (PO) once daily

ARM 8 AZD1775 400 mg Once Daily

Cycle = 21 days. MK-1775 (AZD1775) 225mg by mouth (PO) twice daily

ARM 9 Expansion Cohort 1: AZD1775 225 mg Twice Daily

Cycle = 21 days. MK-1775 (AZD1775) 300mg by mouth (PO) once daily

ARM 10 Expansion Cohort 2: AZD1775 300 mg Once Daily

Cycle = 21 days. MK-1775 (AZD1775) 300 mg by mouth (PO) once daily

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Ovarian carcinoma

Endometrial carcinoma

Mesothelioma

Breast carcinoma

Alveolar soft part sarcoma

Colon adenocarcinoma

Leiomyosarcoma

Pancreatic carcinoma

Prostate carcinoma

Bladder carcinoma

Cervical carcinoma

Cholangiocarcinoma

Endometrial carcinosarcoma

Liposarcoma

Pleomorphic sarcoma

Synovial cell sarcoma

Uterine carcinosarcoma

Non-small cell lung cancer

Papillary serous ovarian carcinoma

Squamous cell carcinoma

Synovial cell carcinoma

Hepatocellular carcinoma

Malignant fibrous histiocytoma sarcoma

Salivary adenocarcinoma

Ewing sarcoma

Fallopian tube carcinoma

Sinonasal leiomyosarcoma

Atypical granular cell paraspinal

Peritoneal carcinoma

Embryonal cell

Appendiceal carcinoma

Tumor Type

ECOG: 0 is normal activity and 1 is symptoms, but ambulatory.

Eastern Cooperative Oncology Score (ECOG)

Median Number of Prior Therapies

Dr. Naoko Takebe

To Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors

Grade 1-2 Anemia

Grade 3 Anemia

Grade 1-2 Lymphopenia

Grade 3 Lymphopenia

Grade 4 Lymphopenia

Grade 1-2 Neutropenia

Grade 3 Neutropenia

Grade 4 Neutropenia

Establish the Safety and Tolerability of Single-agent AZD1775 in Patients With Refractory Solid Tumors

Pre-Treatment (Baseline)

Cycle 1 Day 1, 1 hour post-dose

Cycle 1 Day 1, 2 hours post-dose

Cycle 1 Day 1, 4 hours post-dose

Cycle 1 Day 1, 6 hours post-dose

Cycle 1 Day 1, 8 hours post-dose

Cycle 1 Day 3, pre-dose

Cycle 1 Day 3, 1 hour post-dose

Cycle 1 Day 3, 2 hours post-dose

Cycle 1 Day 3, 4 hours post-dose

Cycle 1 Day 3, 6 hours post-dose

Cycle 1 Day 3, 8 hours post-dose

Cycle 1 Day 5, pre-dose

Cycle 1 Day 5, 1 hour post-dose

Cycle 1 Day 5, 2 hours post-dose

Cycle 1 Day 5, 4 hours post-dose

Cycle 1 Day 5, 6 hours post-dose

Cycle 1 Day 5, 8 hours post-dose

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 200 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated.

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 225 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated.

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 225 mg twice daily on cycle 1 days 1-2, during which the plasma concentrations of AZD1775 were evaluated.

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 250 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated.

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 300 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated.

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 300 mg twice daily on cycle 1 days 1-2, during which the plasma concentrations of AZD1775 were evaluated.

Participants received AZD1775 (MK-1775; adavosertib) by mouth at a starting dose of 400 mg once daily on cycle 1 days 1-5, during which the plasma concentrations of AZD1775 were evaluated.

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).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Debio 0123 in Combination With Carboplatin and Etoposide in Adult Participants With Small Cell Lung Cancer That Recurred or Progressed After Previous Standard Platinum-Based Therapy	NCT05815160	Small Cell Lung...	Debio 0123 Etoposide Carboplatin	18 Years -	Debiopharm International SA
A Study of Debio 0123 in Combination With Temozolomide in Adult Participants With Recurrent or Progressive Glioblastoma and of Debio 0123 in Combination With Temozolomide and Radiotherapy in Adult Participants With Newly Diagnosed Glioblastoma	NCT05765812	Glioblastoma ID... Astrocytoma, Gr...	Debio 0123 Temozolomide Radiotherapy	18 Years -	Debiopharm International SA
Study of Irinotecan and AZD1775, a Selective Wee 1 Inhibitor, in RAS or BRAF Mutated, Second-line Metastatic Colorectal Cancer	NCT02906059	Metastatic Colo...	AZD1775 Irinotecan	18 Years -	NYU Langone Health
AZD1775 for Advanced Solid Tumors	NCT01748825	Solid Tumors	MK-1775 (AZD177...	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for wee1 inhibitor