Clinical trial NCT02264678: Ascending Doses of Ceralasertib in Combination With Chemotherapy and/or Novel Anti Cancer Agents
Official title: A Modular Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ceralasertib in Combination With Cytotoxic Chemotherapy and/or DNA Damage Repair/Novel Anti-cancer Agents in Patients With Advanced Solid Malignancies.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Adv Solid Malig - H&N SCC, ATM Pro / Def NSCLC, Gastric, Breast and Ovarian Cancer
Keywords: ATM deficient, ATM proficient, HER2 negative, Breast, Gastric, Head & Neck, Lung, Ovarian
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-10-15
Enrollment: 357
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed 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.

Eligibility 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

Primary outcomes:
measure: The number of subjects with adverse events/serious adverse events
timeFrame: 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
measure: Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)
timeFrame: From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
measure: Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings
timeFrame: From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of ceralasertib
timeFrame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
measure: Time to observed Cmax (Tmax) for ceralasertib
timeFrame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
measure: Area under the plasma concentration-time curve (AUC) for ceralasertib
timeFrame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)
measure: Maximum Observed Plasma Concentration (Cmax) of Carboplatin
timeFrame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
measure: Time to observed Cmax (Tmax) for Carboplatin
timeFrame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
measure: Area under the plasma concentration-time curve (AUC) for Carboplatin
timeFrame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
measure: Maximum Observed Plasma Concentration (Cmax) of Olaparib
timeFrame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
measure: Time to observed Cmax (Tmax) for Olaparib
timeFrame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
measure: Area under the plasma concentration-time curve (AUC) for Olaparib
timeFrame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
measure: Maximum Observed Plasma Concentration (Cmax) of durvalumab
timeFrame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
measure: Time to observed Cmax (Tmax) for durvalumab
timeFrame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
measure: Area under the plasma concentration-time curve (AUC) for durvalumab
timeFrame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
measure: Assessment of pharmacodynamic biomarker changes
timeFrame: Biopsies of tumour at baseline and last day of dosing
measure: Best objective response
timeFrame: From first dose to confirmed progressive disease (approximately 1 year)
measure: Objective response rate
timeFrame: From first dose to confirmed progressive disease (approximately 1 year)
measure: Percentage change in tumour size
timeFrame: From first dose to confirmed progressive disease (approximately 1 year)
measure: Durable response rate
timeFrame: From first documented response to confirmed progressive disease (approximately 1 year)
measure: Progression free survival
timeFrame: From first dose to confirmed progressive disease (approximately 1 year)
measure: Survival assessment /status
timeFrame: From first dose to confirmed progressive disease (approximately 1 year)
measure: Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures
timeFrame: From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2
measure: Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)
timeFrame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
measure: Module 4 only: Effect of food on ceralasertib absorption by Tmax in a fasted and fed state (Part A)
timeFrame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
measure: Module 4 only: Effect of food on ceralasertib absorption by clearance in a fasted and fed state (Part A)
timeFrame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
measure: Module 4 only: Effect of food on ceralasertib absorption by apparent volume of distribution in a fasted and fed state (Part A)
timeFrame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
measure: Module 4 only: Effect of food on ceralasertib absorption by terminal half-life and terminal rate constant in a fasted and fed state (Part A)
timeFrame: Part A (Cycle 0 Day 2/Day 8/Day 15) - each cycle is of 15 days
measure: Module 4: The number of subjects with adverse events/serious adverse events
timeFrame: From baseline until 28 days after discontinuation of study treatment for Module 4 Part B cohort 1 and cohort 3, or until 90 days after discontinuation of study treatment for Module 4 Part B cohort 2
measure: Module 5 only: Maximum Observed Plasma Concentration (Cmax) of AZD5305
timeFrame: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
measure: Module 5 only: Time to observed Cmax (Tmax) for AZD5305
timeFrame: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
measure: Module 5 only: Area under the plasma concentration-time curve (AUC) for AZD5305
timeFrame: At predefined intervals throughout AZD5305 treatment period (approximately 8 weeks + IP disc)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Irvine
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Newport Beach
country: United States
facility: Research Site
state: California
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Bordeaux
country: France
facility: Research Site
city: Lyon Cedex 08
country: France
facility: Research Site
city: Saint Herblain
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Coventry
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
city: Withington
country: United Kingdom
facility: Research Site
Study officials:
References:
citation: Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.