AZD1775 Combined With Olaparib in Patients With Refractory Solid Tumors

NCT02511795 | Completed Phase 1

• 2 other identifiers: D6010C00005REFMAL 384
• Study Type: interventional
• Target: 128
• Locations: 2 countries
• Sites: 6

Brief 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

Conditions

Refractory Solid Tumours; Relapsed Small Cell Lung Cancer (SCLC)

Keywords

AZD1775; Olaparib; AZD1775 plus Olaparib; Refractory Solid Tumours; Small Cell Lung Cancer (SCLC); Relapsed Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (2)

• Part A: The incidence of dose-limiting toxicities (DLTs)

  The maximum tolerated dose (MTD) of the AZD1775/olaparib combination will be the highest dose level at which less than one-third of patients experience a DLT during Cycle 1. Toxicity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03.

  21 days (Cycle 1 duration)

• Part B: The incidence of treatment-emergent adverse events (TEAEs)

  Treatment-emergent adverse events will be assessed through reports of clinical events and changes from baseline in vital signs and laboratory parameters.

  Up to 12 months

Secondary Outcomes (17)

• Part A: The incidence of treatment-emergent adverse events (TEAEs).

  Up to 12 months

• Part A: Peak plasma concentration (Cmax) of olaparib when given as monotherapy in the olaparib PK sub-study.

  Olaparib plasma concentration will be measured on Day 3 or Day 5 of the olaparib PK sub-study pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose.

• Part A: Area under the plasma concentration versus time curve (AUC) of olaparib when given as monotherapy in the olaparib PK sub-study.

  Olaparib plasma concentration will be measured on Day 3 or Day 5 of the olaparib PK sub-study: pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose.

• Part A: Peak plasma concentration (Cmax) of olaparib when given in combination with AZD 1775.

  Olaparib plasma conc. will be measured pre-dose & 1, 2, 4, 6, 8, & 10 hours post-dose on Days 3, 8, 10, & 15 (or Days 5, 8, 12, & 15) of Cycle 1; & Days 1, 3, & 8 (or Days 1, 5, & 8) of Cycle 2; & Days 3 or 10 (or Days 5 or 12) of Cycle 3.

• Part A: Area under the plasma concentration versus time curve (AUC) of olaparib when given in combination with AZD 1775.

  AUC for olaparib will be measured pre-dose and 1, 2, 4, 6, 8, and 10 hours post-dose on Days 3, 8, 10, and 15 (or Days 5, 8, 12, and 15) of Cycle 1; and Days 1, 3, and 8 (or Days 1, 5, and 8) of Cycle 2; and Days 3 or 10 (or Days 5 or 12) of Cycle 3.

Study Arms (2)

AZD1775 (6 doses/week) + Olaparib

EXPERIMENTAL

In this Arm, AZD1775 will be given twice daily over 3 days (6 doses) on Days 1-3 of Week 1 and Days 8-10 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient 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 AZD1775 and olaparib combined dosing.

Drug: AZD1775; Drug: Olaparib

AZD1775 (10 doses/week) + Olaparib

EXPERIMENTAL

In this Arm, AZD1775 will be given twice daily over 5 days (10 doses) on Days 1-5 of Week 1 and Days 8-12 of Week 2. Olaparib will be given orally BID on Days 1-14. All patients will enter an olaparib sub-study in order to assess multiple dose pharmacokinetics of olaparib prior to entering the main study. In the olaparib PK sub-study patients will take olaparib for 3 consecutive days and venous blood samples will be collected on Day 3. The PK sub-study must be initiated 10 days prior to the Cycle 1 Day 1 administration of the AZD1775 and olaparib combination. The patient 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 AZD1775 and olaparib combined dosing.

Drug: AZD1775; Drug: Olaparib

Interventions

AZD1775 DRUG

AZD1775 will be given twice daily (PO BID) over 3 days (6 doses) on Days 1-3 and 8-10 of each 21 day cycle combined with olaparib PO BID on Days 1-14 of each 21 day cycle. Olaparib will be given orally BID on Days 1-14.

AZD1775 (10 doses/week) + Olaparib; AZD1775 (6 doses/week) + Olaparib

Olaparib DRUG

AZD1775 will be given twice daily (PO BID) over 5 days (10 doses) on Days 1-5 and 8-12 of each 21 day cycle combined with olaparib PO BID on Days 1-14 of each 21 day cycle. Olaparib will be given orally BID on Days 1-14.

AZD1775 (10 doses/week) + Olaparib; AZD1775 (6 doses/week) + Olaparib

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female patients ≥ 18 years of age.
• Any prior palliative radiation therapy 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.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.
• Baseline laboratory values within 7 days of study drug(s) initiation:
• 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) ≥ 51 mL/min
• 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.
• Male patients should be willing to abstain or use barrier contraception (i.e., condoms with a spermicide) for the duration of the study drug exposure and for 3 months after study treatment discontinuation. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential, unless the male patient is abstaining from sexual intercourse.
• Predicted life expectancy ≥ 12 weeks.
• 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.
• Measurable or non-measurable disease according to RECIST v1.1

You may not qualify if:

• Prior treatment with a PARP inhibitor.
• Use of an investigational drug during the past 30 days or 5 half-lives (whichever is longer) prior to 1st dose of study treatment.
• Use of anti-cancer treatment drug ≤ 21 days or 5 half-lives (whichever is shorter) prior to 1st dose of study treatment. For drugs for which 5 half-lives is ≤ 21 days, a minimum of 10 days between termination of the prior treatment and administration of study treatment is required.
• Radiotherapy (except for palliative reasons) within ≤ 21 days prior to study treatment.
• 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. Patients on luteinizing hormone-releasing hormone (LHRH) analogue treatment for more than 6 months are allowed entry into the study and may continue at the discretion of the investigator.
• 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.
• Persistent Grade \>1 toxicity from prior cancer therapy (except alopecia or anorexia).
• Patient has an inability to swallow oral medications. Note: Patients with percutaneous endoscopic gastrostomy (PEG) tube or receiving total parenteral nutrition (TPN) are not eligible.
• 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.
• 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 the 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.
• Caution should be exercised when inhibitors or substrates of P-glycoprotein (P-gp), substrates of CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19 substrates with a narrow therapeutic range are administered with AZD1775.
• \. Herbal preparations are not allowed throughout the study, including but 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.
• \. Any known hypersensitivity or contraindication to the components of the study drug AZD1775 or olaparib.
• \. Patients with either previous or current myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (6)

Research Site

Denver, Colorado, 80218, United States

Location

Research Site

Sarasota, Florida, 34232, United States

Location

Research Site

New York, New York, 10033, United States

Location

Research Site

Nashville, Tennessee, 37203, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• Hamilton EP, Falchook GS, Wang JS, Fu S, Oza AM, Imedio ER, Kumar S, Ottesen L, Mugundu GM, de Bruin EC, O'Connor MJ, Jones SF, Spigel DR, Li BT. Adavosertib in Combination with Olaparib in Patients with Refractory Solid Tumors: An Open-Label, Dose-Finding, and Dose-Expansion Phase Ib Trial. Target Oncol. 2024 Nov;19(6):879-892. doi: 10.1007/s11523-024-01102-8. Epub 2024 Nov 1.

  PMID: 39487373 DERIVED

MeSH Terms

Conditions

Small Cell Lung Carcinoma

Interventions

adavosertib; olaparib

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Study Officials

• Erika P. Hamilton, M.D.

  SCRI Development Innovations, LLC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: July 23, 2015
• First Posted: July 30, 2015
• Study Start: August 6, 2015
• Primary Completion: April 25, 2019
• Study Completion: October 16, 2019
• Last Updated: November 7, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (5); CA (1)