Clinical Trials /

Adavosertib With or Without Olaparib in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

NCT03579316

Description:

This phase II trial studies how well adavosertib with or without olaparib work in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent). Adavosertib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Adavosertib With or Without Olaparib in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
  • Official Title: A Randomized 2-Arm, Non-Comparative Phase 2 Study of AZD1775 Alone or AZD1775 and Olaparib in Ovarian Cancer Patients Who Have Progressed During PARP Inhibition

Clinical Trial IDs

  • ORG STUDY ID: 2016-0677
  • SECONDARY ID: NCI-2018-01105
  • SECONDARY ID: 2016-0677
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03579316

Conditions

  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma

Interventions

DrugSynonymsArms
AdavosertibAZD-1775, AZD1775, MK-1775, MK1775Arm I (adavosertib)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm II (olaparib, adavosertib)

Purpose

This phase II trial studies how well adavosertib with or without olaparib work in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent). Adavosertib and olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the objective response rate (ORR) as determined by Response Evaluation
      Criteria in Solid Tumors version 1.1 (RECIST 1.1) of adavosertib (AZD1775) alone or in
      combination with olaparib in women with recurrent ovarian cancer in whom progression has been
      documented following poly ADP-ribose polymerase (PARP) inhibitor therapy.

      SECONDARY OBJECTIVES:

      I. To evaluate the overall safety and tolerability of AZD1775 alone or in combination with
      olaparib in this population.

      II. To evaluate the disease control rate (DCR) = overall response rate (ORR) plus stable
      disease rate for 16 weeks.

      III. To evaluate the progression free survival (PFS) and overall survival (OS) of this
      population following AZD1775 alone or in combination with olaparib.

      IV. To evaluate the duration of response by RECIST version (v)1.1.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the efficacy of each arm by BRCA-mutation status (BRCA-mt) and homologous
      recombination deoxyribonucleic acid (DNA) repair deficiencies (HRD).

      II. To describe endogenous and dynamic markers of DNA damage response in tumor tissue and
      circulating surrogates, such as circulating tumor cells (CTC), circulating tumor DNA (ctDNA),
      exosomes (cellular/nuclear), cell cycle kinetics (CDKs), and immunophenotype.

      III. To examine genomic alterations associated with response and mechanisms of resistance to
      olaparib and/or AZD1775.

      OUTLINE: Patients are randomized to 1 of 2 arms. If enrollment pauses for 1 arm, patients
      will be assigned to the enrolling arm.

      ARM I: 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.

      ARM II: Patients receive olaparib PO twice daily (BID) on days 1-21 and adavosertib PO QD on
      days 1-3 and 8-10. Cycles repeat every 21 days in the absence of disease progression or
      unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (adavosertib)Active ComparatorPatients receive adavosertib PO QD on days 1-5 and 8-12. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Adavosertib
Arm II (olaparib, adavosertib)ExperimentalPatients receive olaparib PO BID on days 1-21 and adavosertib PO QD on days 1-3 and 8-10. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Adavosertib
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Has read and understands the informed consent form and has given written informed
             consent prior to any study procedures.

          -  Histologically confirmed recurrent epithelial ovarian, primary peritoneal, or
             fallopian tube cancer for which there is no known or established treatment available
             with curative intent.

          -  Have demonstrated progressive disease while taking a PARP inhibitor as a previous
             therapy or within 6 months of completing PARP inhibitor therapy. Response to prior
             PARP inhibitor(i) is not required.

          -  Prior PARP therapy could have been administered as either treatment for recurrent
             disease or as maintenance following prior treatment.

          -  Measurable disease according to RECIST v1.1.

          -  Adequate archived primary or metastatic tumor tissue collected before the prior PARP
             therapy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.

          -  Absolute neutrophil count (ANC) >=1500/L (within 14 days of study drug[s] initiation).

          -  Hemoglobin (Hgb) >= 10 g/dL with no blood transfusion in the past 14 days (within 14
             days of study drug[s] initiation).

          -  Platelets >= 100,000/L (within 14 days of study drug[s] initiation).

          -  Alanine transaminase (ALT) and aspartate transaminase (AST) =< 2.5 x upper limit of
             normal (ULN) or =< 5 x ULN if known hepatic metastases (within 14 days of study
             drug[s] initiation).

          -  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
             well documented Gilbert's syndrome (within 14 days of study drug[s] initiation).

          -  Patients should have calculated or measured creatinine clearance of >= 50 mL/min.

          -  Women who are not of child-bearing potential and fertile females of childbearing
             potential who agree to use adequate contraceptive measures, who are not breastfeeding,
             and who have a negative serum pregnancy test within 3 days prior to the start of study
             treatment.

          -  Predicted life expectancy >= 16 weeks.

          -  Willingness and ability to comply with study and follow-up procedures.

        Exclusion Criteria:

          -  Prior Treatment:

               -  PARP inhibitor: Most oral PARP inhibitors (the immediate prior therapy) have a
                  half-life for which 5 half-lives is =< 21 days. Thus, a minimum of 10 days
                  between termination of the prior treatment and administration of olaparib and/or
                  AZD1775 treatment is required. In the event a PARP inhibitor has a longer
                  half-life where 5 half-lives is >= 21 days, treatment of olaparib and/or AZD1775
                  should not begin for 5 half-lives or at least 21 days, whichever is shorter.

               -  Any hormonal therapy directed at the malignant tumor must be discontinued at
                  least one week prior to registration (study enrollment). Continuation of hormone
                  replacement therapy is permitted.

               -  Any other prior therapy directed at the malignant tumor, including immunologic
                  agents, must be discontinued at least three weeks prior to first dose of study
                  drug (6 weeks for nitrosoureas or mitomycin C).

          -  Major surgical procedures =< 28 days of beginning study treatment, or minor surgical
             procedures =< 7 days. No waiting period required following port-a-cath placement.

          -  Grade > 1 toxicity from prior therapy (except alopecia or anorexia).

          -  Patient has an inability to swallow oral medications and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication. Note: Patient may not have a percutaneous endoscopic gastrostomy (PEG)
             tube or be receiving total parenteral nutrition (TPN).

          -  Known central nervous system (CNS) disease other than neurologically stable, treated
             brain metastases - defined as metastasis having no evidence of progression or
             hemorrhage for at least 3 weeks after treatment (including brain radiotherapy). Must
             be off any systemic corticosteroids for the treatment of brain metastases for at least
             14 days prior to enrollment.

          -  Patient has had a prescription or non-prescription drugs or other products known to be
             sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index,
             or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued
             2 weeks prior to day -3 of dosing and withheld throughout the study until 2 weeks
             after the last dose of study drug. Co-administration of aprepitant or fosaprepitant
             during this study is prohibited.

          -  Herbal preparations are not allowed throughout the study. These herbal medications
             include but are not limited to: St. John's wort, kava, ephedra (mahung), gingko
             biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng. Patients
             should stop using these herbal medications 7 days prior to first dose of study
             treatment.

          -  Any known hypersensitivity or contraindication to the components of the study drug
             AZD1775 or olaparib.

          -  Any of the following cardiac diseases currently or within the last 6 months as defined
             by New York Heart Association (NYHA) >= class 2. a. Unstable angina pectoris; b.
             Congestive heart failure; c. Acute myocardial infarction; d. Conduction abnormality
             not controlled with pacemaker or medication; e. Significant ventricular or
             supraventricular arrhythmias (patients with chronic rate- controlled atrial
             fibrillation in the absence of other cardiac abnormalities are eligible).

          -  AZD1775 should not be given to patients who have a history of Torsades de pointes
             unless all risk factors that contributed to Torsades have been corrected. AZD1775 has
             not been studied in patients with ventricular arrhythmias or recent myocardial
             infarction.

          -  Patients with resting corrected QT interval (specifically QTc calculated using the
             Fridericia formula [QTcF]) > 470 msec from a single electrocardiogram (ECG) performed
             at study entry or congenital long QT syndrome.

          -  Pregnant or breast-feeding.

          -  Serious active infection at the time of study entry, or another serious underlying
             medical condition that would impair the ability of the patient to receive study
             treatment.

          -  Presence of other active invasive cancers.

          -  Psychological, familial, sociological, or geographical conditions that do not permit
             compliance with protocol.

          -  Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with
             features suggestive of MDS/AML.

          -  Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate defined as complete response (CR) or partial response (PR), assessed by Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 6 months
Safety Issue:
Description:Will be computed and presented along with an exact 90% confidence interval using the method of Clopper and Pearson.

Secondary Outcome Measures

Measure:Disease control rate defined as the percentage of patients with a confirmed best overall response of complete response or partial response, or a best overall response of stable disease
Time Frame:Up to 6 months
Safety Issue:
Description:The point estimate per treatment arm and the 95% Pearson-Clopper confidence interval for the objective response rates will be provided. Logistic regression analyses will be performed to assess the influence of baseline covariates in an exploratory manner.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

October 16, 2019