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

Conditions

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

Eligibility Criteria

Sex

ALL

Age

18 Years - 130 Years

Healthy Volunteers

Not accepted

Interventions

• Administration of ceralasertib — DRUG
  An oral formulation of ceralasertib will be used. In Module 2 Part A1, patients will receive a single dose of ceralasertib on Day 1, followed by 4 to 6 days washout, before multiple dosing.
• Administration of ceralasertib in combination with olaparib — DRUG
  An oral formulations of ceralasertib and olaparib will be used. In Module 2 Part A2, patients will receive either a single or twice daily dose of ceralasertib followed by 4 to 6 days washout, before multiple dosing with ceralasertib and olaparib. In Module 2 Part B, patients will receive ceralasertib and olaparib at the dose, frequency and schedule recommended from Module 2 Part A2. Cycle 0 may be omitted at the discretion of the sponsor.
• Administation of ceralasertib in combination with durvalumab — DRUG
  An oral formulation of ceralasertib will be used. Durvalumab is given via IV infusion. In Module 3 Part A, patients will receive an initial single dose of ceralasertib on Day 1, followed by multiple dosing in combination with durvalumab. In Module 3 Serial Tumour Biopsy Extension and Part B expansion cohorts, patients will receive ceralasertib at the dose, frequency and schedule recommended from Module 3 Part A, in combination with durvalumab.
• Administration of ceralasertib monotherapy — DRUG
  Module 4 Part A and Module 4 Part B Cohort 3: During C0, patients will receive ceralasertib monotherapy orally once a day on 3 non-consecutive days and ceralasertib twice a day on 5 consecutive days. After the patients have completed C0 (Part A) they may transition to Module 4 Part B cohort 3 where they will continue to receive ceralasertib monotherapy
• Administration of ceralasertib and olaparib — DRUG
  Module 4 Part B Cohort 1: After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with olaparib as decided by the investigator.
• Administration of ceralasertib and durvalumab — DRUG
  Module 4 Part B Cohort 2: After completion of Part A (C0), the patient may transition to Part B and be allocated to receive ceralasertib in combination with durvalumab as decided by the investigator.
• Administration of ceralasertib in combination with AZD5305 — DRUG
  An oral formulations of ceralasertib and AZD5305 will be used. In Module 5 Part A, patients will receive a single dose of ceralasertib on cycle 0 Day 1 as per dose level cohort. In Module 5 Part B, patients will receive ceralasertib and AZD5305: C1 onwards (as per dose level cohort allocated).
• Administration of ceralasertib in combination with carboplatin — DRUG
  An oral formulation of ceralasertib will be used. In Module 1 Part A, patients will receive a single dose of ceralasertib on Day 1, followed by multiple dosing in combination with carboplatin. A maximum of 6 cycles (21 days per cycle) of treatment will be given. In Module 1 Part B, patients will receive ceralasertib and carboplatin at the dose, frequency and schedule recommended from Module 1 Part A.

Study Details

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.

Key Dates

Start date

Oct 31, 2014

Status verified

May 2026

Primary completion

Mar 4, 2025

Completion

Jun 30, 2026

Study Design

Enrollment

354 participants (actual)

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Arms

• Experimental: Module 2 Part A1
  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.
• Experimental: Module 2 Part A2
  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.
• Experimental: Module 2 Part B1
  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.
• Experimental: Module 2 Part B2
  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.
• Experimental: Module 2 Part B3
  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.
• Experimental: Module 2 Part B4
  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.
• Experimental: Module 3 Part A
  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.
• Experimental: Module 3 Part B
  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.
• Experimental: Module 2 Part B5
  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.
• Experimental: Module 4 (FE/QT)
  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.
• Experimental: Module 5 Part A
  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.
• Experimental: Module 5 Part B
  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.
• Experimental: Module 1 Part A
  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).
• Experimental: Module 1 Part B
  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.

Primary Outcome Measure

The number of subjects with adverse events/serious adverse events [ Time Frame: From baseline until 28 days after discontinuation of study treatment for Module 1, 2 and 5 or until 90 days after discontinuation of study treatment for Module 3 and 4 ]

Locations (8)

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