Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents

AstraZeneca

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer

Treatments: Drug: Administration of ceralasertib in combination with olaparib; Drug: Administration of ceralasertib monotherapy; Drug: Administation of ceralasertib in combination with durvalumab; Drug: Administration of ceralasertib in combination with carboplatin; Drug: Administration of ceralasertib; Drug: Administration of ceralasertib and durvalumab; Drug: Administration of ceralasertib in combination with AZD5305; Drug: Administration of ceralasertib and olaparib

Study type: Interventional

Funder types: Industry

Identifiers

NCT02264678

D5330C00004

2014-002233-66 (EudraCT Number)

Details and patient eligibility

About

This is a modular, phase I/ phase 1 b, open-label, multicentre study of ceralasertib administered orally in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced malignancies. The study design allows an investigation of optimal combination dose of ceralasertib with other anti-cancer treatments, with intensive safety monitoring to ensure the safety of the patients. The initial combination to be investigated is ceralasertib with carboplatin. The second combination to be investigated is ceralasertib with Olaparib. The third combination to be investigated is ceralasertib with durvalumab. The fourth module will investigate the effect of food on ceralasertib absorption and the effect of ceralasertib on ECG parameter. The fifth module to be investigated is ceralasertib with AZD5305.

Full description

This is a modular, phase I, two part, open-label, multicentre study of ceralasertib, administered orally, in combination with cytotoxic chemotherapy regimens and/or novel anti-cancer agents, to patients with advanced/metastatic solid malignancies. The study design allows an escalation of the dose of ceralasertib in combination with the standard dose and schedule of either cytotoxic chemotherapies and/or novel anti-cancer agents, with intensive safety monitoring to ensure the safety of the patients. There are two parts to each combination module of this study; part A, dose escalation and an optional part B, cohort expansions in particular patient groups. The initial combination module will be with Carboplatin (module 1). The second combination will be with Olaparib (module 2). The third combination will be with durvalumab (module 3), the fourth combination will be AZD5305 (Module 5). The option to start further combination modules will be the decision of the Safety Review Committee (SRC), based on emerging preclinical data and, safety and tolerability information from the initial combination. Combinations of ceralasertib with novel anti-cancer agents may also be explored. Once a minimally biologically active dose of ceralasertib, for that combination module, has been identified from part A of that module, the SRC may decide to commence part B if deemed to be necessary. This may include cohort expansions of specific patient groups to explore preliminary anti-tumour activity or the effect of food or particular drug combinations on drug pharmacokinetics. The fourth module will investigate the effect of food on ceralasertib absorption and whether ceralasertib has an effect on QT.

Enrollment: 466 estimated patients

Sex: All

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Principal Inclusion criteria:

• Aged at least 18
• The presence of a solid malignant tumour that is not considered appropriate for further standard treatment
• Module 2 Part B study expansions, and Module 3: patients must have a tumour at least 1 cm in size that can be measured using a CT or MRI scan
• Module 2 Part B All (except B5): No previous treatment with PARP inhibitor.
• Module 2 Part B1 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM deficient tumours
• Module 2 Part B2 Study expansion: advanced gastric adenocarcinoma (including GEJ) patients with ATM proficient tumours
• Module 2 Part B3 Study expansion: Second or thrid line HER2 negative breast cancer
• Module 2 Part B4 Study expansion: Second or third line triple negative breast cancer (TNBC)
• Module 2 Part B5 Study expansion: BRCAm or RAD51C/Dm or PALB2m or HRD positive status ovarian cancer patient who are Platinum Sensitive Relapsed and have previously progressed on a licensed PARPi
• Module 3: advanced recurrent or metastatic non-small cell lung cancer, or head and neck squamous cell carcinoma
• Module 4: any advanced solid tumours except gastric, gastro-oesophageal, oesophageal or colorectal cancer with a small bowel resection
• Module 4: Ability to comply with an overnight fast of at least 10 hours prior to dosing and 4 hours after dosing as mandated, and ability to eat a high fat meal as mandated
• Module 5 All: Ovarian fallopian tube or primary peritonial cancer, previous treatment with PARP inhibitor, platinum-sensitive relapsed ovarian cancer
• Module 5 Part B: known or suspected BRCA mutation, PALB2 mutation, RAD51C/D mutation or HRD positive status

Principal exclusion criteria

• A diagnosis of ataxia telangiectasia
• Prior exposure to an ATR inhibitor
• Bad reaction to ceralasertib
• Module 2: Contra-indicated for treatment with olaparib
• Module 3: Contra-indicated for treatment with durvalumab
• Module 4: Mean resting corrected QT interval (QTc) >470 msec or history of familial long QT syndrome.
• Module 4: Patients with type I or type II diabetes
• Module 5: Known hypersensitivity to PARP including AZD5305

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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466 participants in 14 patient groups

Module 2 Part A1

Experimental group

Description:

Module 2 Part A1: ascending doses of ceralasertib will be administered alone to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD) to take into Module 2 Part A2.

Treatment:

Drug: Administration of ceralasertib

Module 2 Part A2

Experimental group

Description:

Module 2 Part A2: ascending doses of ceralasertib will be administered in combination with olaparib to patients to define the dose, frequency and schedule of ceralasertib and olaparib to take into Module 2 Part B.

Treatment:

Drug: Administration of ceralasertib in combination with olaparib

Module 2 Part B1

Experimental group

Description:

Module 2 Part B1: Patients with second line 'ATM deficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Treatment:

Drug: Administration of ceralasertib in combination with olaparib

Module 2 Part B2

Experimental group

Description:

Module 2 part B2: Patients with second line 'ATM proficient' gastric adenocarcinoma including GEJ adenocarcinoma will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Treatment:

Drug: Administration of ceralasertib in combination with olaparib

Module 2 Part B3

Experimental group

Description:

Module 2 Part B3: Patient with second or third line breast cancer with BRCA mutations (somatic or germline), excluding HER2 positive breast cancer will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Treatment:

Drug: Administration of ceralasertib in combination with olaparib

Module 2 Part B4

Experimental group

Description:

Module Part B4: Patients with second or third line triple negative breast cancer with no known BRCA mutations. This expansion will be enriched for patients with disease harbouring a HRR-related gene mutation (HRRm) will receive ceralasertib with olaparib, at dose, frequency and schedule recommended from Module 2 Part A2.

Treatment:

Drug: Administration of ceralasertib in combination with olaparib

Module 3 Part A

Experimental group

Description:

Module 3 Part A: cohort escalation of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients to define the dose, frequency and schedule of ceralasertib and durvalumab to take into Module 3 Part B. Additionally, Module 3 Part A will include a serial tumour biopsy cohort to evaluate the Proof of Mechanism of ceralasertib in HNSCC and NSCLC patients.

Treatment:

Drug: Administation of ceralasertib in combination with durvalumab

Module 3 Part B

Experimental group

Description:

Module 3 Part B: cohort expansions of ceralasertib in combination with durvalumab in HNSCC or NSCLC patients at dose, frequency and schedule from Module 3 Part A.

Treatment:

Drug: Administation of ceralasertib in combination with durvalumab

Module 2 Part B5

Experimental group

Description:

Patients with BRCA mutant or RAD51C/D mutant (either germline or somatic) or HRD-positive status epithelial ovarian, fallopian tube, or primary peritoneal cancer according to local testing. Patients must be platinum sensitive and previously progressed on a licensed PARPi. The cohort will be split into 2 groups: Cohort 1 - without intervening chemotherapy following progression on a PARPi, Cohort 2 - with intervening chemotherapy following progression on a PARPi. Patients will receive ceralasertib and olaparib, at the RP2D dose, frequency and schedule established from Module 2 Part A2.

Treatment:

Drug: Administration of ceralasertib in combination with olaparib

Module 4 (FE/QT)

Experimental group

Description:

Ceralasertib monotherapy will be administered on a number of days during Cycle 0 to assess the effect of food on ceralasertib absorption and effect of ceralasertib on ECG parameters under various conditions (fasted, fed, steady state). From C1 onwards, patients who participated in C0 will be allocated to either ceralasertib in combination with olaparib or durvalumab, or ceralasertib monotherapy and assessed for safety.

Treatment:

Drug: Administration of ceralasertib and olaparib

Drug: Administration of ceralasertib and durvalumab

Drug: Administration of ceralasertib monotherapy

Module 5 Part A

Experimental group

Description:

Module 5 Part A: ascending doses of ceralasertib will be administered in combination with AZD5305 to patients to define the MTD, RP2D. In case this first dose level is not tolerated, alternative schedules will be evaluated.

Treatment:

Drug: Administration of ceralasertib in combination with AZD5305

Module 5 Part B

Experimental group

Description:

Module 5 Part B: cohort expansions of ceralasertib in combination with AZD5305 in ovarian patients at dose, frequency and schedule from Module 5 Part A.

Treatment:

Drug: Administration of ceralasertib in combination with AZD5305

Module 1 Part A

Experimental group

Description:

Module 1 Part A: ascending doses of ceralasertib in combination with carboplatin AUC5 will be administered to patients to define the maximum tolerated dose (MTD) and/or a continuous, tolerable Recommended Dose (RD).

Treatment:

Drug: Administration of ceralasertib in combination with carboplatin

Module 1 Part B

Experimental group

Description:

Module 1 Part B: patients with advanced lung adenocarcinoma with low expression of ATM will receive ceralasertib and carboplatin, at the dose, frequency and schedule recommended from Module 1 Part A.

Treatment:

Drug: Administration of ceralasertib in combination with carboplatin