A Phase 1 interventional study of Adavosertib and Cisplatin in Cervical Carcinoma, Endometrioid Adenocarcinoma and Malignant Female Reproductive System Neoplasm, sponsored by National Cancer Institute (NCI). Terminated at 8 sites in 2 countries. Open to female participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-02-20.
Sponsored by National Cancer Institute (NCI) · Phase 1, Interventional, and Treatment
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.
PRIMARY OBJECTIVE:
I. To determine the recommended phase II dose (RP2D) and safety profile of adavosertib (AZD1775) in combination with radiotherapy and concurrent cisplatin in patients with gynecological cancers.
SECONDARY OBJECTIVES:
I. To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin.
II. To evaluate the pharmacodynamic effects of AZD1775 when administered in combination with radiotherapy and concurrent cisplatin (in particular, for the 15 patients treated in an expansion cohort at the RP2D).
III. To obtain preliminary information about the progression-free survival, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or clinical progression, of AZD1775 in combination with standard radiotherapy and concurrent cisplatin in women with gynecological cancer.
OUTLINE: This is a dose-escalation study of adavosertib.
Patients undergo external beam radiation therapy on days 1-5 and receive adavosertib orally (PO) on days 1, 3, and 5 or once daily (QD) on days 1-5 and cisplatin intravenously (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.
After completion of study treatment, patients are followed up at 28 days and then every 4 months for 2 years.
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
Newly diagnosed epithelial carcinoma of the upper 1/3 vagina, T1-3, N0/1, M0/1
Hemoglobin >= 9 g/dL
Exclusion Criteria:
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
Given PO
Also known as: AZD-1775, AZD1775, MK-1775, MK1775
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
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
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.
Time frame: Up to week 5
Frequency and Severity of AZD1775 Toxicity Events in Patients With Gynecological Cancer in Combination With Standard RT and Concurrent Cisplatin
To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.
Time frame: Up to 2 years
Pharmacodynamic Effects of AZD1775 in Combination With RT and Concurrent Cisplatin
To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in combination with radiotherapy and concurrent cisplatin. Pharmacodynamic biomarkers will include: pCDC2, Ki67, γH2AX, pH3, and CC3. Associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.
Time frame: Up to 2 years
Progression-free Survival
To obtain preliminary information about the progression-free survival of AZD1775 in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer. Progression is defined a clinical or radiological using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
This study was performed at 5 academic centers in the United States (four sites) and Canada (one site). It enrolled participants from May 2018 to July 2020.
| Milestone | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 |
|---|---|---|
| Started | 5 | 5 |
| Completed | 3 | 4 |
| Not completed | 2 | 1 |
| Withdrew: Withdrawal by subject | 2 | 1 |
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.
| Participants | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 |
|---|---|---|
| Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities | NA | NA |
To determine the acute and late toxicity of AZD1775 when administered to patients with gynecological cancer in combination with standard radiotherapy and concurrent cisplatin. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a subanalysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.
| events | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 |
|---|---|---|
| All Grade 1-2 Toxicities | 46 | 53 |
| Related Grade 1-2 Toxicities | 37 | 36 |
| All Grade 3-4 Toxicities | 8 | 3 |
| Related Grade 3-4 Toxicities | 8 | 3 |
To evaluate the pharmacodynamic effects of AZD1775 drugs when administered in combination with radiotherapy and concurrent cisplatin. Pharmacodynamic biomarkers will include: pCDC2, Ki67, γH2AX, pH3, and CC3. Associations between pharmacokinetic data with toxicity profiles will be performed primarily using descriptive statistics; however, logistic regression may be used if warranted.
No measurements were reported for this outcome.
To obtain preliminary information about the progression-free survival of AZD1775 in combination with radiotherapy and concurrent cisplatin in women with locally advanced gynecological cancer. Progression is defined a clinical or radiological using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
| Participants | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 |
|---|---|---|
| 4 Months Post Treatment — Alive and progression-free post-treatment | 3 | 4 |
| 4 Months Post Treatment — Lost to Follow-Up | 0 | 0 |
| 2 Years Post Treatment — Alive and progression-free post-treatment | 3 | 3 |
| 2 Years Post Treatment — Lost to Follow-Up | 0 | 1 |
Collected over 2 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | 0/4 (0%) | 1/4 (25%) | 4/4 (100%) |
| Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | 0/5 (0%) | 1/5 (20%) | 5/5 (100%) |
| Event | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 |
|---|---|---|
| Grade 3 DiarrheaGastrointestinal disorders | 1/4 | 0/5 |
| Grade 3 Lymphocyte Count DecreasedBlood and lymphatic system disorders | 0/4 | 1/5 |
| Event | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 |
|---|---|---|
| NauseaGastrointestinal disorders | 4/4 | 5/5 |
| DiarrheaGastrointestinal disorders | 3/4 | 4/5 |
| VomitingGastrointestinal disorders | 1/4 | 4/5 |
| FatigueGeneral disorders | 3/4 | 3/5 |
| HypomagnesemiaMetabolism and nutrition disorders | 3/4 | 0/5 |
| ThrombocytopeniaInvestigations | 3/4 | 0/5 |
| AnemiaBlood and lymphatic system disorders | 3/4 | 0/5 |
| AnorexiaMetabolism and nutrition disorders | 3/4 | 1/5 |
| DermatitisInjury, poisoning and procedural complications | 0/4 | 3/5 |
| Abdominal painGastrointestinal disorders | 2/4 | 1/5 |
| Age, Continuous(years) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| Median | 48 (43 to 78) | 53 (35 to 63) | 50.5 (35 to 78) |
| Sex: Female, Male(Participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| Female | 5 | 5 | 10 |
| Male | 0 | 0 | 0 |
| Ethnicity (NIH/OMB)(Participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 |
| Not Hispanic or Latino | 4 | 5 | 9 |
| Unknown or Not Reported | 1 | 0 | 1 |
| Race (NIH/OMB)(Participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 0 | 0 | 0 |
| White | 3 | 5 | 8 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 1 | 0 | 1 |
| Region of Enrollment(participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| Canada | 2 | 1 | 3 |
| United States | 3 | 4 | 7 |
| ECOG Performance Status(Participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| 0 | 1 | 4 | 5 |
| 1 | 4 | 1 | 5 |
| Primary Site(Participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| Cervical | 4 | 5 | 9 |
| Uterine | 1 | 0 | 1 |
| Prior Therapy(Participants) | Treatment (Radiation Therapy, AZD1775 3 Days/Week, Cisplatin) Dose Level 1 | Treatment (Radiation Therapy, AZD1775 2 Days/Week, Cisplatin) Dose Level -1 | Total |
|---|---|---|---|
| Surgery | 5 | 5 | 10 |
| Radiation | 0 | 0 | 0 |
3 further baseline measures are reported on the registry.
Documents are hosted by the registry — open the source record to download them.
This study is terminated, as verified in Jan 2024. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
National Cancer Institute (NCI)