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Cervical CarcinomaPhase 1NCT03345784

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

A Phase 1 study testing Adavosertib, Cisplatin and External Beam Radiation Therapy in people with Cervical Carcinoma and Endometrioid Adenocarcinoma, run by National Cancer Institute (NCI) at 8 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older, women only
What is being tested?
Adavosertib, Cisplatin and External Beam Radiation Therapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
8 sitesin 2 countries
Study dates
29 May 2018to 10 May 2022
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 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • Blood transfusions are allowed at any time during the screening, treatment or follow-up period, according to the center recommendations
  • Prothrombin time (PT)/partial thromboplastin time (PTT)/international normalized ratio (INR) =< 1.5 upper limit of normal (ULN)
  • Total bilirubin: serum bilirubin within normal limits (WNL) or =< 1.5 x ULN in patients with liver metastases; or total bilirubin =< 3.0 x ULN with direct bilirubin WNL in patients with documented Gilbert's syndrome
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN) or =< 5 x ULN if known hepatic metastases
  • Creatinine clearance (CrCl) >= 60 mL/min as calculated by the Cockcroft-Gault method
  • Patients must be able to swallow whole capsules
  • The effects of AZD1775 on the developing human fetus are unknown; the preclinical chromosomal aberrations assays have shown potential to induce chromosomal aberrations; in addition, cisplatin and radiotherapy are known to be teratogenic; for this reason, women of child-bearing potential must agree to use two birth control methods (two barrier methods or a barrier method plus a hormonal method) or abstinence prior to study entry, for the duration of study participation prior to study entry, for the duration of study participation, and for 4 months after coming off study; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately
  • Females with child-bearing potential must have had a negative serum pregnancy test result =< 28 days prior to the first dose of study treatment
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • 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
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  • 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

Trial locations and contacts

8 sites in 2 countries.

8 sites in 2 countries

United States6 sites

  • UCHealth University of Colorado Hospital

    Aurora, Colorado, 80045

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • University of Kentucky/Markey Cancer Center

    Lexington, Kentucky, 40536

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

    New Brunswick, New Jersey, 08903

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

  • University of California Davis Comprehensive Cancer Center

    Sacramento, California, 95817

Other trials in United States

Canada2 sites

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

  • BCCA-Vancouver Cancer Centre

    Vancouver, British Columbia, V5Z 4E6

Other trials in Canada

About this study

Official title: A Phase I Study of the Wee 1 Kinase (Wee 1) Inhibitor AZD1775 in Combination With Radiotherapy and Cisplatin in Cervical, Upper Vaginal and Uterine Cancers (10041848, 10008224, 10008238, 10046888, 10014735)

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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.

Being tested
Adavosertib, Cisplatin, External Beam Radiation Therapy
Medical subject headings
Uterine Cervical Neoplasms, Carcinoma, Endometrioid, Vaginal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AdavosertibDrug

    Also called AZD-1775, AZD1775, MK-1775, MK1775

    Given PO

  • CisplatinDrug

    Also called Abiplatin, Blastolem, Briplatin, CDDP

    Given IV

  • External Beam Radiation TherapyRadiation

    Also called Definitive Radiation Therapy, EBRT, External Beam Radiation, External Beam Radiotherapy

    Undergo external beam radiation therapy

Study groups in NCT03345784
Study groupRoleWhat they receive
Treatment (radiation therapy, adavosertib, cisplatin)ExperimentalPatients 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.
Receives: Drug: Adavosertib; Drug: Cisplatin; Radiation: External Beam Radiation Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Up to week 5

Secondary outcomes (3)

  1. 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.

    Measured: Up to 2 years

  2. 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.

    Measured: Up to 2 years

  3. 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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Nov 2017
  2. Study start29 May 2018
  3. Primary completion10 May 2022
  4. Study completion10 May 2022

Why it stopped: Inadequate accrual rate

Resources

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03345784
Sponsor's protocol ID
NCI-2017-00038
Other IDs
NCI-2017-00038, 2013-01765, PHL-087, 10132, 10132, UM1CA186644
Status last verified
Jan 2024
First submitted
16 Nov 2017
Last updated
20 Feb 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Adavosertib, Cisplatin and External Beam Radiation Therapy in people with Cervical Carcinoma and Endometrioid Adenocarcinoma, run by National Cancer Institute (NCI) at 8 sites in 2 countries.

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 24 inclusion and 12 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: stopped early, as of the sponsor's last update on 20 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States, Canada. 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 6 Jun 2023). 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?

Recommended Phase 2 Dose Defined as the Dose Level With < 1/6 Patients With Dose Limiting Toxicities (time frame: Up to week 5). 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 NCT03345784.

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 20 Feb 2024.

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