Adavosertib in Treating Patients with Recurrent Uterine Serous Carcinoma

Status: Active

Description

This phase II trial studies how well adavosertib works in treating patients with uterine serous carcinoma that has come back. Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Participants must have histologically or cytologically confirmed recurrent or persistent uterine serous carcinoma. For the purposes of this study, uterine carcinomas (with the exception of carcinosarcomas) that have any component that is considered serous will be considered a uterine serous carcinoma. Participants with carcinosarcomas (even if there is a serous component), however, will not be considered eligible for this study.
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured per RECIST 1.1 criteria.
  • Participants must have had one prior platinum-based chemotherapy regimen for management of advanced or metastatic uterine serous carcinoma. Chemotherapy administered only in conjunction with primary radiotherapy (RT) as a radiosensitizer should not count as a systemic regimen. There is no restriction on the number of prior lines of therapy a participant may have previously received.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Absolute neutrophil count >= 1,500/mcL.
  • Hemoglobin >= 9 g/dL.
  • Platelets >= 100,000/mcL.
  • Total bilirubin =< upper limit of normal (ULN) or =< 1.5 x ULN in patients with liver metastases or well-documented Gilbert’s syndrome.
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN or =< 5 x ULN in patients with liver metastases.
  • Creatinine =< 1.5 x ULN OR creatinine clearance >= 45 mL/min/1.73 m^2 as calculated by the Cockcroft-Gault method for participants with creatinine levels above institutional normal.
  • Willingness to release archival tissue for research purposes.
  • The effects of AZD1775 on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from 2 weeks prior to study entry and for 1 month after study drug discontinuation. Patients of child-bearing potential should not be breastfeeding, and must have a negative serum or urine pregnancy test within 3 days prior to the start of study treatment. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

  • Participants who have had chemotherapy, radiotherapy, or investigational therapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of AZD1775, or those who have not recovered to grade 1 from adverse events (excluding alopecia or anorexia) due to agents administered more than 3 weeks earlier. Participants may not have had hormonal therapy within 2 weeks of the first dose of AZD1775.
  • Participants who are receiving any other investigational agents.
  • Participants who have microsatellite instability (MSI)-high or mismatch repair (MMR)-deficient tumors will not be eligible unless they have already received prior therapy with pembrolizumab or another PD1/PD-L1 immune checkpoint inhibitor or are deemed not to be a candidate for immune checkpoint therapy.
  • Participants with known brain metastases or other central nervous system (CNS) disease should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Participants with treated brain metastases that have no evidence of progression or hemorrhage for at least 2 weeks after treatment will be allowed on study.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775.
  • Participants may not have had prior receipt of a cell cycle checkpoint inhibitor (e.g., Chek1, Wee1, or ATR inhibition).
  • Participants receiving any medications or substances that are sensitive CYP3A4 substrates or are CYP3A4 substrates with a narrow therapeutic index, or which are moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued two weeks prior to day 1 of dosing and withheld through the study until 2 weeks after the last dose of study drug. Co-administration of aprepitant or fosaprepitant during this study is prohibited. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin, and lovastatin, is also prohibited in this study.
  • Participants must not have undergone major surgical procedures within 28 days of beginning study treatment or minor surgical procedures within 7 days of beginning study treatment. Port-a-cath placement will be allowed within a 7 day window of starting study treatment.
  • Participants must be able to swallow oral medication and may not have a percutaneous endoscopic gastrostomy (PEG) tube, be receiving total parenteral nutrition (TPN), or be dependent on intravenous (IV) fluid support.
  • Participants with any of the following cardiac diseases currently or within the last 6 months as defined by the New York Heart Association (NYHA) >= class 2 will not be eligible: * Unstable angina pectoris. * Congestive heart failure. * Acute myocardial infarction. * Conduction abnormality not controlled with pacemaker or medication. * Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
  • Participants with a mean resting corrected QT interval (QTc) >= 470 msec at study entry, or congenital long QT syndrome.
  • Participants with any concomitant or prior invasive malignancies are ineligible with the following exceptions: * Treated limited-stage basal cell or squamous cell carcinoma of the skin. * Carcinoma in situ of the breast or cervix. * Prior cancer treated with curative intent with no evidence of recurrent disease 3 years following diagnosis and judged by the investigator to be at low risk of recurrence.
  • 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 AZD1775 is an agent with an unknown 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, breastfeeding should be discontinued if the mother is treated with AZD1775.
  • Known human immunodeficiency virus (HIV)-positive participants are ineligible because of the potential for pharmacokinetic interactions of antiretroviral medications with AZD1775 and the potential for an increased risk of lethal infections for these participants when treated with marrow-suppressive therapy.
  • Because the composition, pharmacokinetic (PK), and metabolism of many herbal supplements are unknown, the concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, cannabis, St. John’s wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, and ginseng). Participants should stop herbal medications at least 7 days prior to first dose of AZD1775.

Locations & Contacts

Massachusetts

Boston
Brigham and Women's Hospital
Status: Active
Contact: Joyce Fu Liu
Phone: 617-632-5269
Email: JLIU1@PARTNERS.ORG
Dana-Farber Cancer Institute
Status: Active
Contact: Joyce Fu Liu
Phone: 617-632-5269
Email: JLIU1@PARTNERS.ORG

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. Assess the activity of adavosertib (AZD1775), as measured by the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST)1.1 criteria, in women with recurrent or persistent high-grade serous carcinoma of the uterus.

II. Assess the activity of AZD1775, as measured by the rate of progression-free survival at 6 months (PFS6), in women with recurrent or persistent high-grade serous carcinoma of the uterus.

SECONDARY OBJECTIVES:

I. Assess additional measures of activity of AZD1775, including clinical benefit rate (response rate plus stable disease [SD] x 6 months), duration of response, and progression-free survival, in women with recurrent or persistent high-grade serous carcinoma of the uterus.

II. Assess the safety profile of AZD1775, as assessed by adverse events, in women with recurrent or persistent high-grade serous carcinoma of the uterus.

EXPLORATORY OBJECTIVES:

I. Perform targeted next generation sequencing on archival tumor specimens to determine whether alterations in cell cycle, homologous recombination pathway members, or oncogenic drivers, correlate with the activity of AZD1775 in women with uterine serous carcinoma.

OUTLINE:

Patients receive adavosertib orally (PO) once daily (QD) on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Joyce Fu Liu

Trial IDs

Primary ID 18-316
Secondary IDs NCI-2018-02459
Clinicaltrials.gov ID NCT03668340