Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers

NCT03345784 | Terminated Phase 1 Results DMC FDA Drug

• 5 other identifiers: NCI-2017-000382013-01765PHL-08710132UM1CA186644
• Study Type: interventional
• Target: 10
• Locations: 2 countries
• Sites: 8

Brief Summary

This phase I trial studies the side effects and best dose of adavosertib when given together with external beam radiation therapy and cisplatin in treating patients with cervical, vaginal, or uterine cancer. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. External beam radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving adavosertib, external beam radiation therapy, and cisplatin may work better in treating patients with cervical, vaginal, or uterine cancer.

Conditions

Cervical Carcinoma; Endometrioid Adenocarcinoma; Malignant Female Reproductive System Neoplasm; Recurrent Cervical Carcinoma; Stage I Uterine Corpus Cancer AJCC v7; Stage I Vaginal Cancer AJCC v6 and v7; Stage IA Uterine Corpus Cancer AJCC v7; Stage IB Cervical Cancer AJCC v6 and v7; Stage IB Uterine Corpus Cancer AJCC v7; Stage IB2 Cervical Cancer AJCC v6 and v7; Stage II Cervical Cancer AJCC v7; Stage II Uterine Corpus Cancer AJCC v7; Stage II Vaginal Cancer AJCC v6 and v7; Stage IIA Cervical Cancer AJCC v7; Stage IIB Cervical Cancer AJCC v6 and v7; Stage III Cervical Cancer AJCC v6 and v7; Stage III Uterine Corpus Cancer AJCC v7; Stage III Vaginal Cancer AJCC v6 and v7; Stage IIIA Cervical Cancer AJCC v6 and v7; Stage IIIA Uterine Corpus Cancer AJCC v7; Stage IIIB Cervical Cancer AJCC v6 and v7; Stage IIIB Uterine Corpus Cancer AJCC v7; Stage IIIC Uterine Corpus Cancer AJCC v7; Vaginal Carcinoma

Outcome Measures

Primary Outcomes (1)

• Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities

  To determine the recommended phase II dose (RP2D) and safety profile of AZD1775 in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.

  Up to week 5

Secondary Outcomes (3)

• Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin

  Up to 2 years

• Pharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin

  Up to 2 years

• Progression-free Survival

  From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

Study Arms (1)

Treatment (radiation therapy, adavosertib, cisplatin)

EXPERIMENTAL

Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib PO on days 1, 3, and 5 or QD on days 1-5 and cisplatin IV over 1 hour on day 1 or 3. Cycles repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.

Drug: Adavosertib; Drug: Cisplatin; Radiation: External Beam Radiation Therapy

Interventions

Adavosertib DRUG

Given PO

Also known as: AZD-1775, AZD1775, MK-1775, MK1775

Treatment (radiation therapy, adavosertib, cisplatin)

Cisplatin DRUG

Given IV

Also known as: Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin

Treatment (radiation therapy, adavosertib, cisplatin)

External Beam Radiation Therapy RADIATION

Undergo external beam radiation therapy

Also known as: Definitive Radiation Therapy, EBRT, External Beam Radiation, External Beam Radiotherapy, External Beam Radiotherapy (conventional), External Beam RT, external radiation, External Radiation Therapy, external-beam radiation, Radiation, External Beam, Teleradiotherapy, Teletherapy, Teletherapy Radiation

Treatment (radiation therapy, adavosertib, cisplatin)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have one of the following biopsy proven gynecological cancer and a decision to treat with radiotherapy and concurrent cisplatin chemotherapy (RT-CT)
• Newly diagnosed epithelial carcinoma of the cervix, cT1B-3B, N0/1, M0/1
• Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
• Newly diagnosed epithelial carcinoma of the upper 1/3 vagina, T1-3, N0/1, M0/1
• Patient may have small volume metastatic disease in para-aortic or supraclavicular lymph nodes or at other metastatic sites as long as, in the best judgment of the treatment team, a radical course of pelvic radiotherapy is warranted to assure local disease control
• Newly diagnosed endometrioid adenocarcinoma of the uterus, cT1-3, N0/1, M0 unsuitable for primary surgery because of the extent of local disease; these patients are eligible if a prior decision has been made to treat radically with neoadjuvant chemoradiation followed by surgery or further radiotherapy (including brachytherapy) depending on response
• Central pelvis or sidewall recurrence of epithelial carcinoma of the cervix of endometrioid adenocarcinoma of the uterus after previous surgery without previous pelvic radiotherapy
• Patients must be planned to receive whole pelvic radiotherapy to a total dose of 45 Gy or greater
• Patients must be able to receive weekly cisplatin
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky \>= 60%)
• Life expectancy of greater than 3 months
• Leukocytes \>= 3,000/mcL
• Absolute neutrophil count \>= 1,500/mcL
• Platelets \>= 100,000/mcL
• Hemoglobin \>= 9 g/dL

You may not qualify if:

• Patients who have received any radiotherapy or chemotherapy for their current gynecological cancer
• Patients who received prior pelvic radiotherapy for any indication
• Patients who have a mean resting correct corrected QT (QTc) interval using the Fridericia formula (QTcF) \> 470 msec (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome; AZD1775 should not be given to patients who have a history of Torsades de pointes unless all risk factors contributed to Torsades have been corrected; AZD1775 has not been studied in patients with ventricular arrhythmias or recent myocardial infarction
• Patients requiring para-aortic radiotherapy
• Patients who are receiving any other investigational agents or anticancer therapy concurrently or within 4 weeks (i.e. 28 days)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or cisplatin
• Uncontrolled intercurrent illness including, but not limited to, myocardial infarction within 6 months, congestive heart failure, symptomatic congestive heart failure, unstable angina pectoris, active cardiomyopathy, unstable ventricular arrhythmia, uncontrolled hypertension, uncontrolled psychotic disorders, serious infections, active peptic ulcer disease, active liver disease or cerebrovascular disease with previous stroke, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because AZD1775 and chemoradiation are agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775 and cisplatin, breastfeeding must be discontinued if the mother is treated with AZD1775 and cisplatin; these potential risks may also apply to other agents used in this study
• Patients with another uncontrolled malignancy; patients with a previous malignancy, treated curatively and without evidence of disease relapse are eligible
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD1775; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• History of active clinically significant bleeding
• History of bowel obstruction or malabsorption syndromes (within the last 3 months) which might limit the absorption of the study drug

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (8)

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

New Brunswick, New Jersey, 08903, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

BCCA-Vancouver Cancer Centre

Vancouver, British Columbia, V5Z 4E6, Canada

Location

University Health Network-Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

MeSH Terms

Conditions

Uterine Cervical Neoplasms; Carcinoma, Endometrioid; Vaginal Neoplasms

Interventions

adavosertib; Cisplatin; 1,2-diaminocyclohexaneplatinum II citrate; Platinum; Congresses as Topic; Radiation

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Endometrial Neoplasms; Ovarian Neoplasms; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine System Diseases; Vaginal Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Metals, Heavy; Elements; Transition Elements; Metals; Organizations; Health Care Economics and Organizations; Physical Phenomena

Limitations and Caveats

The main limitation of our study is the small number of patients enrolled due to premature closure; yet the study showed the limiting toxicities of this triplet combination.

Results Point of Contact

• Title: Dr. Stephanie Lheureux, PI
• Organization: University Health Network, Princess Margaret Cancer Centre

stephanie.lheureux@uhnresearch.ca

416-946-2818

Study Officials

• Stephanie Lheureux

  University Health Network Princess Margaret Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 16, 2017
• First Posted: November 17, 2017
• Study Start: May 29, 2018
• Primary Completion: May 10, 2022
• Study Completion: May 10, 2022
• Last Updated: February 20, 2024
• Results First Posted: June 6, 2023

Record last verified: 2024-01

Locations

US (6); CA (2)