Clinical Trials /

Adavosertib, External Beam Radiation Therapy, and Cisplatin in Treating Patients With Cervical, Vaginal, or Uterine Cancer

NCT03345784

Description:

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.

Related Conditions:
  • Cervical Carcinoma
  • Endometrial Endometrioid Adenocarcinoma
  • Vaginal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Adavosertib, External Beam Radiation Therapy, and Cisplatin in Treating Patients With Cervical, Vaginal, or Uterine Cancer
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00038
  • SECONDARY ID: NCI-2017-00038
  • SECONDARY ID: 2013-01765
  • SECONDARY ID: PHL-087
  • SECONDARY ID: 10132
  • SECONDARY ID: 10132
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT03345784
  • NCT ALIAS: NCT01958658

Conditions

  • Endometrioid Adenocarcinoma
  • 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

Interventions

DrugSynonymsArms
AdavosertibAZD-1775, AZD1775, MK-1775, MK1775Treatment (radiation therapy, adavosertib, cisplatin)
CisplatinAbiplatin, 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, PlatosinTreatment (radiation therapy, adavosertib, cisplatin)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      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. Courses 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.
    

Trial Arms

NameTypeDescriptionInterventions
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. Courses repeat each week for up to 5 weeks in the absence of disease progression of unacceptable toxicity.
  • Adavosertib
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          -  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

               -  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

        Exclusion Criteria:

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose defined as the dose level with < 1/6 patients with dose limiting toxicities
Time Frame:Up to week 5
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective response assessed according to local investigator
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Pharmacodynamic effects of adavosertib when given in combination with radiation therapy and cisplatin
Time Frame:Up to 2 years
Safety Issue:
Description:Pharmacodynamic biomarkers will include: phosphorylated (p)CDC2, Ki67, gammaH2AX, 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.
Measure:Progression-free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:
Measure:Incidence of acute adverse events assessed by National Cancer Institute (NCI) Clinical Trials Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (version 5.0 beginning April 1, 2018)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Incidence of late adverse events assessed by NCI CTCAE version 4.0 (version 5.0 beginning April 1, 2018)
Time Frame:Up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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