Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

Clinical trial: AZD1775 Combined With Olaparib in Patients With Refractory Solid Tumors

Summary: The purpose of this Phase 1b, multi-centre, dose escalation study is to find the maximum tolerated dose (MTD) of AZD1775 combined with olaparib in patients with refractory solid tumours

Detailed description: This is a Phase Ib, multi-centre study of AZD1775 combined with olaparib administered orally in patients with refractory solid tumours, or as first-line sequential combination therapy for extensive disease (ED) small-cell lung cancer (SCLC). There are 3 parts to the study design:
  Part A: Dose Escalation Part B: Dose Expansion Part C: Expansion in first-line ED SCLC
  In Part A, patients with refractory solid tumours will be assessed for safety, tolerability, and pharmacokinetics (PK) of AZD 1775 when combined with olaparib. Different dose levels will be administered to identify the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D).
  The dose expansion part (Part B) will further explore the safety, PK, and efficacy of the MTD/RP2D and dosing schedule, through cohorts organized by tumour type with molecular biomarkers of interest in the following treatment cohorts:
  Ovarian Cancer
  -  Twenty patients with confirmed BRCA1 and/or BRCA2 mutation. Patients must have exhausted all standard treatment options, however must not have received prior treatment with a PARP-inhibitor.
  -  Twenty patients with confirmed BRCA wild-type status. Patients must have exhausted all standard treatment options for advanced disease (recurrent or metastatic).
  Triple Negative Breast Cancer
  -  Patients must have previously been treated with at least 1 chemotherapy-containing regimen for advanced disease (recurrent or metastatic).
  -  Approximately 15 biomarker positive (amplification of at least one of the following genes: CCNE1, MYC, MYCL, or MYCN) and 15 biomarker negative patients will be treated, with the potential to recruit up to an additional 20 patients.
  Second-Line Small Cell Lung Cancer
  -  Patients must have previously been treated with no more than one chemotherapy-containing regimen for advanced disease (recurrent or metastatic), and relapsed at least 90 days following completion of that treatment.
  -  Approximately 15 biomarker positive (amplification of at least one of the following genes: CCNE1, MYC, MYCL, or MYCN) and 15 biomarker negative patients will be treated, with the potential to recruit up to an additional 20 patients.
  Part C is a dose expansion arm in first-line SCLC patients with ED who have demonstrated an objective complete response (CR), partial response (PR) or stable disease with measurable tumour shrinkage following two cycles of a Standard of Care chemotherapy regimen containing etoposide and platinum. The combination of AZD 1775 and olaparib will be evaluated as a first-line sequential combination therapy.
  An olaparib pharmacokinetic (PK) sub-study will precede the combined treatment with AZD1775 and olaparib for all patients. In the PK sub-study olaparib will be taken orally BID for 3 days and venous blood samples will be collected on Day 3 for assessment of the multiple dose pharmacokinetics of single agent olaparib. Patients will experience a short gap in treatment (approximately 4-5 days) between Day 3 of the olaparib PK sub-study and Cycle 1 Day 1 of the combination treatment.
  Patients will continue to receive treatment with AZD1775 and Olaparib until disease progression, intolerable toxicity, or discontinuation criteria have been met.

Eligibility: Principal Inclusion Criteria for All Patients
  1. Male and female patients ≥ 18 years of age.
  2. Any prior radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment. For patients in Part C, this criteria applies during Stage 2 screening only.
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.
  4. Baseline laboratory values within 7 days of study drug(s) initiation for Parts A and B and within 3 days for Part C Stage 2:
  ANC ≥ 1500/μL Haemoglobin (Hgb) ≥10 g/dL without transfusion in the past 28 days Platelets ≥ 100,000/μL Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN or ≤ 5 x ULN if known liver metastases.
  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.
  Serum creatinine ≤1.5 x ULN and creatinine clearance (CrCl) ≥ 51mL/min
  5. Female patients who are not of child-bearing potential, and fertile females of childbearing potential who agree to use two highly effective forms of contraception in combination from 2 weeks prior to study treatment and until 1 month after study treatment discontinuation, are not breastfeeding, and must have a negative serum or urine pregnancy test within 28 days of study treatment and confirmed prior to the start of study treatment on first day of dosing.
  6. Male patients and their partners, who are sexually active and of childbearing potential, must agree to use two highly effective forms of contraception throughout the period of taking study treatment and for 3 months after the last dose(s) to prevent pregnancy in a partner.
  7. Predicted life expectancy ≥ 12 weeks. For patients in Part C the timing of this assessment is applied from the beginning of Stage 2
  Inclusion criteria specific to Part A
  8. Histologically confirmed refractory solid tumour for which there is no known or established treatment available with curative intent, after at least one course of systemic therapy for locally advanced or metastatic disease including chemotherapy, targeted therapy or hormonal therapy.
  9. Measurable or non-measurable disease according to RECIST v1.1
  Inclusion criteria specific to Part B
  10. The patient must fit into one of the follow tumour specific cohorts: (a) Ovarian cancer (b) Triple negative breast cancer, (c) Small-cell lung cancer.
  11. Provision of an adequate tissue sample is mandatory for study eligibility.
  12. Measurable disease according to RECIST v1.1
  Inclusion criteria specific to Part C
  13. Stage 1 of Part C: First-line patients with extensive disease SCLC defined as histologically or cytologically confirmed diagnosis of SCLC with documented extensive disease.
  14. Stage 2 of Part C: First-line patients with extensive disease SCLC who have achieved a response (CR or PR) or stable disease with measurable tumour shrinkage after two cycles of three weeks each of etoposide plus platinum.
  15. Measurable disease according to RECIST v1.1.
  Principal Exclusion Criteria
  1. No prior treatment with a PARP inhibitor.
  2. Use of an investigational drug during the past 30 days or 5 half-lives (whichever is longer) prior to 1st dose of study treatment.
  3. Anti-cancer treatment drug ≤21 days or 5 half-lives (whichever is longer) prior to 1st dose of study treatment.
  4. Radiotherapy (except for palliative reasons) within ≤ 21 days prior to study treatment.
  5. No other anti-cancer therapy (except for palliative local radiotherapy), biological therapy, or other novel agent is permitted while the patient is receiving study medication.
  6. Major surgical procedures ≤ 28 days of beginning study treatment, or minor surgical procedures ≤ 7 days. Patients must have recovered from any of the effects of any major surgery. No waiting period required following port-a-cath placement.
  7. Persistent Grade >1 toxicity from prior cancer therapy (except alopecia or anorexia).
  8. Patient has an inability to swallow oral medications.
  9. Known malignant central nervous system (CNS) disease other than neurologically stable, treated brain metastases, defined as metastasis having no evidence of progression or haemorrhage for at least 2 weeks after treatment. Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.
  10. Patient has had 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 olaparib PK sub-study dosing and withheld throughout the study until 2 weeks after the last dose of study drug. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and lovastatin are prohibited in this study. Co-administration of aprepitant or fosaprepitant during this study is prohibited.
  11. Herbal preparations are not allowed throughout the study. These herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), 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.
  12. Any known hypersensitivity or contraindication to the components of the study drug AZD1775 or olaparib.
  13. Patients with either previous or current myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML.
  14. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2.
  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)
  15. Patient with mean resting corrected QT interval (specifically QTc calculated using the Fridericia formula [QTcF]) ≥470 msec for female patients and ≥450 msec for male patients from 3 electrocardiograms (ECGs) performed within 5 minutes apart at study entry or congenital long QT syndrome. For patients in Part C, the ECG assessments will be obtained at the beginning of the Stage 2 screening.
  16. Pregnant or breastfeeding women.
  17. Serious known active infection at the time of enrolment, or another serious underlying medical condition that would impair the ability of the patient to receive study treatment.
  18. Presence of other known active invasive cancers.
  19. Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
  20. Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection
  21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with protocol.
  22. Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
  23. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).

Relevance to patient case: not relevant