Clinical Trials /

Olaparib With Cediranib or AZD6738 for the Treatment of Advanced or Metastatic Germline BRCA Mutated Breast Cancer

NCT04090567

Description:

This phase II trial studies how well olaparib with cediranib or AZD6738 works in treating patients with germline BRCA mutated breast cancer that has spread to other places in the body (advanced or metastatic). Olaparib, cediranib, and AZD6738 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib With Cediranib or AZD6738 for the Treatment of Advanced or Metastatic Germline BRCA Mutated Breast Cancer
  • Official Title: Overcoming PARP Inhibitor Resistance in BRCA Germline Mutation Positive Advanced Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2018-0062
  • SECONDARY ID: NCI-2019-04148
  • SECONDARY ID: 2018-0062
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04090567

Conditions

  • Advanced Breast Carcinoma
  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • Germline BRCA1 Gene Mutation
  • Germline BRCA2 Gene Mutation
  • HER2/Neu Negative
  • Metastatic Breast Carcinoma
  • Prognostic Stage III Breast Cancer AJCC v8
  • Prognostic Stage IIIA Breast Cancer AJCC v8
  • Prognostic Stage IIIB Breast Cancer AJCC v8
  • Prognostic Stage IIIC Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
CediranibAZD2171Arm I (olaparib plus cediranib)
CeralasertibAZD6738Arm II (olaparib plus ceralasertib)
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Arm I (olaparib plus cediranib)

Purpose

This phase II trial studies how well olaparib with cediranib or AZD6738 works in treating patients with germline BRCA mutated breast cancer that has spread to other places in the body (advanced or metastatic). Olaparib, cediranib, and AZD6738 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the objective response rate (ORR) of olaparib plus cediranib and olaparib plus
      ceralasertib (AZD6738) combinations in patients with advanced or metastatic breast cancer
      with germline BRCA (breast cancer susceptibility gene) mutations who have been previously
      treated with PARP inhibitors.

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability of olaparib in combination with cediranib and in
      combination with AZD6738 in patients with advanced or metastatic breast cancer with germline
      BRCA mutations.

      II. To assess duration of response (DOR) to treatment. III. To assess best response. IV. To
      estimate progression free survival (PFS).

      EXPLORATORY OBJECTIVES:

      I. To evaluate BRCA1 expression at baseline and on progression. II. To evaluate hypoxia
      markers at baseline and on progression. III. To evaluate levels of angiogenesis/ inflammatory
      markers including VEGF (vascular endothelial growth factor) at baseline and on progression.

      IV. To evaluate novel markers of resistance and response to PARP inhibitor in baseline and
      upon progression of disease in tumor tissue that are identified by the investigator's basic
      science collaborator's ongoing studies in vitro and in vivo.

      V. To evaluate circulating tumor deoxyribonucleic acid (DNA) at baseline and on progression.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive olaparib orally (PO) twice daily (BID) and cediranib PO once daily
      (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Patients receive olaparib PO BID on days 1-28 and ceralasertib PO QD on days 1-7.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (olaparib plus cediranib)ExperimentalPatients receive olaparib PO BID and cediranib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cediranib
  • Olaparib
Arm II (olaparib plus ceralasertib)ExperimentalPatients receive olaparib PO BID on days 1-28 and ceralasertib PO QD on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Ceralasertib
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Provision of informed consent prior to any study specific procedures

          -  Advanced/metastatic HER2 negative, BRCA germline positive breast cancer. Estrogen
             receptor positive (ER+) patients must have progressed on a prior endocrine therapy or
             are considered inappropriate for any Food and Drug Administration (FDA) approved
             endocrine therapies for ER+ breast cancer

          -  Hemoglobin (Hgb) >= 10.0 g/dL (measured within 28 days [baseline screening] and 1 day
             prior to initiation of cycle 1 day 1 administration of study treatment) with no blood
             transfusion in the past 28 days prior to the administration

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days [baseline
             screening] and 1 day prior to initiation of cycle 1 day 1 administration of study
             treatment) with no granulocyte colony stimulating factor (GCSF) administration within
             28 days prior to administration of study treatment

          -  Platelet count >= 100 x 10^9/L (measured within 28 days [baseline screening] and 1 day
             prior to initiation of cycle 1 day 1 administration of study treatment)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28
             days [baseline screening] and 1 day prior to initiation of cycle 1 day 1
             administration of study treatment)

          -  Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) =< 3.0 x
             institutional upper limit of normal unless liver metastases are present in which case
             they must be =< 5 x ULN (measured within 28 days [baseline screening] and 1 day prior
             to initiation of cycle 1 day 1 administration of study treatment)

          -  Patients must have creatinine clearance estimated using the Cockcroft-Gault creatinine
             clearance equation of >= 51 mL/min, and a random or 24 hours urine protein creatinine
             (UPC) ratio =< 1 (measured within 28 days [baseline screening] and 1 day prior to
             initiation of cycle 1 day 1 administration of study treatment)

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Patients must have life expectancy >= 16 weeks

          -  Negative urine or serum pregnancy test within 28 days of study treatment and confirmed
             prior to treatment on cycle 1 day 1 and during the study for child bearing potential
             women

               -  Female subjects must either be of non-reproductive potential (i.e.,
                  post-menopausal by history: >= 60 years old and no menses for >= 1 year without
                  an alternative medical cause; OR history of hysterectomy, OR history of bilateral
                  tubal ligation, OR history of bilateral oophorectomy) or must have a negative
                  serum pregnancy test upon study entry and be using highly effective contraception
                  (that is, methods with a failure rate of less than 1% per year) for both male and
                  female subjects if the risk of conception exists (Note: The effects of the trial
                  treatment on the developing human fetus are unknown; thus, women of childbearing
                  potential and men must agree to use highly effective contraception, defined in E
                  or as stipulated in national or local guidelines). Highly effective contraception
                  must be used 30 days prior to first trial treatment administration, for the
                  duration of trial treatment, and at least for 1 month after stopping trial
                  treatment

          -  Patients is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations

          -  Patient has measurable disease, per Response Evaluation Criteria in Solid Tumors
             (RECIST) version (v) 1.1. At least one lesion, not previously irradiated, that can be
             accurately measured at baseline as >= 10 mm in the longest diameter (except lymph
             nodes which must have short axis >= 15 mm) with computed tomography (CT) or magnetic
             resonance imaging (MRI)

          -  Willingness to undergo baseline biopsy of metastatic lesion (repeat biopsy at
             progression/or end of the study is optional)

          -  Willingness to have research blood draw at baseline and at progression/end of the
             study

          -  Patient should have previously treated with any PARP inhibitor and must have remained
             on treatment for >= 4 months prior to progression of disease

          -  Able to swallow and retain oral medications and without gastrointestinal (GI)
             illnesses that would preclude absorption of cediranib, olaparib or AZD6738

          -  Additional inclusion criteria for olaparib + cediranib. Adequately controlled blood
             pressure (systolic blood pressure [SBP] =< 140 mmHg; diastolic blood pressure [DBP] =<
             90 mmHg) on maximum of 3 antihypertensive medications. Patients must have a blood
             pressure (BP) of =< 140/90 mmHg taken in the clinic setting by a medical professional
             within 2 weeks prior to starting study. It is strongly recommended that patients who
             are on three antihypertensive medications be followed by a cardiologist or a primary
             care physician for management of BP (blood pressure) while on study

          -  Urine protein quantitative value of =< 30 mg/dl in urinalysis or =< 1+ on dipstick.
             (If criteria cannot be met, 24-hour urine collection can be done to calculate total
             protein excretion. If a 24 hour total urinary protein excretion is < 1000 mg, the
             participant may be included

          -  Adequately controlled thyroid function, with no symptoms of thyroid dysfunction

        Exclusion Criteria:

          -  Patients who have had chemotherapy or RT (radiation therapy) within 3 weeks prior to
             start of the study agents or persisting >= grade 2 Common Terminology Criteria for
             Adverse Events (CTCAE) toxicity (except alopecia and grade 2 peripheral neuropathy)
             from previous anti-cancer treatment(s), or those who have not recovered from adverse
             events due to agents administered more than 3 weeks earlier

          -  Patients received any other investigational agents within the past 4 weeks

          -  Patients with untreated brain metastases, spinal cord compression, or evidence of
             symptomatic brain metastases or leptomeningeal disease as noted on computed tomography
             (CT) or magnetic resonance imaging (MRI) scans should be excluded from this clinical
             trial. Patient with known and treated brain metastases is allowed in this study if
             they fulfil the following criteria: The lesions have improved or remained stable
             radiographically and clinically for at least 6 weeks after completion of brain
             irradiation or stereotactic brain radiosurgery and off steroids for at least 6 weeks.
             (For olaparib + AZD6738 Arm 2; patients can be on steroids not more than 10 mg/day if
             started 4 weeks prior to initiation of study drug)

          -  Patients who have received prior inhibitor of VEGF signaling

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cediranib or olaparib or AZD6738

          -  Participants receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 are ineligible, unless discontinues within the washout period (2
             weeks for CYP3A4 inhibitors and 4 weeks for CYP3A4 inducers). Dihydropyridine
             calcium-channel blockers are permitted for management of hypertension. In addition,
             patients enrolled in olaparib + AZD6738 arm, co-administration of study drug with
             substrates of OATP1B1 and Pgp (P-glycoprotein) inhibitor or inducer is prohibited

          -  Current use of natural herbal products or other complementary alternative medications
             (CAM) or "folk remedies" should be discontinued 7 days prior to the initiation of
             study drugs

          -  Patients with concomitant or prior invasive malignancies within the past 5 years.
             Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin
             or carcinoma in situ of the breast or cervix are eligible

          -  Uncontrolled inter-current illness including, but not limited to, extensive
             interstitial bilateral lung disease on high resolution computed tomography (HRCT)
             scan, ongoing or active infection, or psychiatric illness/social situations that would
             limit compliance with study requirements

          -  Congestive heart failure requiring treatment (New York Heart Association grade >= 2;
             left ventricular ejection fraction [LVEF] < 50% as determined by multi-gated
             acquisition [MUGA] scan or echocardiogram [ECHO]) (Only for Arm 1 olaparib +
             cediranib)

          -  History of myocardial infarction, stroke or transient ischemic attack within 6-12
             months. Current condition requiring concurrent use of drugs or biologics with
             anti-arrhythmic or pro-arrhythmic potential

          -  History of hypertensive crisis or hypertensive encephalopathy within 3 years

          -  Clinically significant peripheral vascular disease or vascular disease (abdominal
             aortic aneurysm (> 5 cm) or aortic dissection). If known history of abdominal aortic
             aneurysm with >= 4 cm in diameter, all the following criteria must be met:

               -  An ultrasound (US) within the last 6 months will be required to document that it
                  is =< 5 cm

               -  Patient must be asymptomatic from the aneurysm

          -  A major surgical procedure, open biopsy, or significant traumatic injury within 28
             days prior to starting cediranib (percutaneous/endobronchial biopsies are allowed).
             The patient must have recovered from any effects of any major surgery and surgical
             wound should have healed prior to starting treatment

          -  Patients may not have current signs and/or symptoms of bowel obstruction within 3
             months prior to starting study drugs, except if it was a temporary incident (improved
             within < 24 hours [hrs] with medical management)

          -  History of hemoptysis or any significant bleeding within the last 1 month prior to
             enrollment

          -  Presence of cavitation of central pulmonary lesion

          -  Intra-abdominal abscess within the 3 months prior to enrollment. Patient with history
             of GI perforation. History of abdominal fistula will be considered eligible, if the
             fistula was surgically repaired, there has been no evidence of fistula for at least 6
             months prior to starting treatment, and patient is deemed to be at low risk of
             recurrent fistula

          -  Patients may not have current dependency on intravenous (IV) hydration or total
             parenteral nutrition (TPN)

          -  Patients may have features suggestive of myelodysplastic syndrome (MDS) or acute
             myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if
             clinically indicated

          -  As judged by the investigator, any evidence of severe or uncontrolled systemic
             diseases, active bleeding diatheses, renal transplant, or active infection including
             any patient known to have hepatitis B, hepatitis C and human immunodeficiency virus
             (HIV). Screening for chronic conditions is not required

          -  Any condition that, in the opinion of the treating investigator would interfere with
             evaluation of the investigational product or interpretation of subject safety or study
             results

          -  Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study medication

          -  Prior exposure to an AZD 6738 and cediranib

          -  Patients with uncontrolled seizure

          -  Any of the following cardiac criteria:

               -  Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible
                  cardiac conditions, as judged by the investigator (e.g., unstable ischemia,
                  uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT
                  interval by Fridericia (QTcF) prolongation > 450 milli-second, or patients with
                  congenital long QT syndrome or family history of unexplained sudden death under
                  40 years of age)

               -  Any clinically important abnormalities in rhythm, conduction or morphology of
                  resting ECG (e.g., complete left bundle branch block, third degree heart block)

          -  Patients at risk of brain perfusion problems, e.g., carotid stenosis

          -  Patients with relative hypotension (< 100/60 mm Hg) or clinically relevant orthostatic
             hypotension (>= 20 beats per minute change in pulse including a fall in blood pressure
             of >= 20 mm Hg associated with dizziness, syncope, and blurred vision, from lying down
             or sitting to standing). Uncontrolled hypertension requiring clinical intervention

          -  Breast feeding/lactating/pregnant women

          -  Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation

          -  Progressed on or recurred within 1 months of completing platinum-based chemotherapy in
             metastatic setting

          -  Additional exclusion criteria for olaparib + cediranib: Patients may not have evidence
             of coagulopathy or bleeding diathesis. Therapeutic anticoagulation for prior
             thromboembolic events is permitted. The clinical indication for therapeutic
             anticoagulation must be clearly documented prior to enrollment and must be discussed
             with the principal investigator (PI). Given the increased risk of serious bleeding
             from cediranib, patients who are on more than or equal to 2 anti-thrombotic agents,
             including but not limited to anti-platelet agents (nonsteroidal anti-inflammatory drug
             [NSAID]s/aspirin, clopidogrel), heparin, low molecular weight heparin (LMWH),
             warfarin, and a direct thrombin inhibitor, will be excluded

          -  Additional exclusion criteria for olaparib + AZD6738: A diagnosis of ataxia
             telangiectasia

          -  Major surgery within 3 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:Defined as proportion of patients with reduction in tumor burden (complete response [CR] or partial response [PR] as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The exact two-sided 95% confidence interval for the ORR will be reported.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:PFS will be estimated using the Kaplan-Meier method with the 95% confidence intervals (CIs). Will analyze aggregate data from selected arms of the trial using Cox proportional hazards and logistic regression to identify study factors related to outcomes including response and PFS. Hazard ratios and odds ratios with their 95% confidence intervals and p-values will be reported. Model assumptions will be verified.
Measure:Duration of response (DOR)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:DOR will be estimated using the Kaplan-Meier method with the 95% CIs. Will analyze aggregate data from selected arms of the trial using Cox proportional hazards and logistic regression to identify study factors related to outcomes including response and PFS. Hazard ratios and odds ratios with their 95% confidence intervals and p-values will be reported. Model assumptions will be verified.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated