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

Phase 2Active Not RecruitingNCT02264678

AstraZeneca357 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Interventions

Administration of ceralasertibDRUG

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 olaparibDRUG

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 durvalumabDRUG

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 monotherapyDRUG

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 olaparibDRUG

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 durvalumabDRUG

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 AZD5305DRUG

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 carboplatinDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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

Locations (28)

Research Site

Duarte, California, United States

Research Site

Irvine, California, United States

Research Site

Los Angeles, California, United States

Research Site

Los Angeles, California, United States

Research Site

Newport Beach, California, United States

Research Site

Boston, Massachusetts, United States

Research Site

New York, New York, United States

Research Site

Philadelphia, Pennsylvania, United States

Research Site

Bordeaux, France

Research Site

Lyon, France

...and 18 more locations

Outcomes

Primary Outcomes

The number of subjects with adverse events/serious adverse events

Number of patients with adverse events and with serious adverse events including abnormal clinical observations, DLT, abnormal Electrocardiogram (ECG) parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline.

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

Module 4 only: Effect of food on ceralasertib absorption by Intensive PK assessments after a single oral dose of ceralasertib (Part A)

Intensive PK sampling at defined timepoints to measure Geometric mean and 90% CI for the ratio of fed: fasted in area under the plasma concentration time curve from zero to the last measurable time point (AUC0-t), area under the plasma concentration time curve from zero to infinity (AUC)

Time frame: From 0h to 24h on Day 2 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days

Module 4 only: Effect of ceralasertib on ECG parameters (HR, PR, QRS and QTcF) by ECG recordings

Change from baseline HR, PR, QRS and QTcF (ΔHR, ΔPR, ΔQRS and ΔQTcF) Categorical outliers for QTcF, HR, PR, and QRS Frequency of treatment emergent T and U wave abnormalities If a substantial HR effect is observed (i.e., the absolute value of the largest least squares \[LS\] mean ΔHR is greater than 10bpm in the by-time point analysis), other correction methods such as individualised and optimised individualised HR corrected QT interval (QTcI) will be explored and compared. The method that removes the HR dependence of the QT interval most efficiently will be chosen as the primary correction method.

Time frame: From 0h to 24h on Day 2, Day 8 and Day15 in Cycle 0 (Part A) - Cycle 0 is 15 days

Secondary Outcomes

Maximum Observed Plasma Concentration (Cmax) of ceralasertib

Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Cmax.

Time frame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)

Time to observed Cmax (Tmax) for ceralasertib

Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Tmax.

Time frame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)

Area under the plasma concentration-time curve (AUC) for ceralasertib

Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive AUC.

Time frame: At predefined intervals throughout the ceralasertib treatment period (approximately 8 weeks for Module 1 and 16 weeks + IP disc. for Module 2+3)

Maximum Observed Plasma Concentration (Cmax) of Carboplatin

Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Cmax.

Time frame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)

Time to observed Cmax (Tmax) for Carboplatin

Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Tmax.

Time frame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)

Area under the plasma concentration-time curve (AUC) for Carboplatin

Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive AUC.

Time frame: At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)

Maximum Observed Plasma Concentration (Cmax) of Olaparib

Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Cmax.

Time frame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)

Time to observed Cmax (Tmax) for Olaparib

Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Tmax.

Time frame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)

Area under the plasma concentration-time curve (AUC) for Olaparib

Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive AUC.

Time frame: At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)

Maximum Observed Plasma Concentration (Cmax) of durvalumab

Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Cmax.

Time frame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)

Time to observed Cmax (Tmax) for durvalumab

Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Tmax.

Time frame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)

Area under the plasma concentration-time curve (AUC) for durvalumab

Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive AUC.

Time frame: At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)

Assessment of pharmacodynamic biomarker changes

Evaluation of ceralasertib activity in the tumour by assessment of pharmacodynamic biomarker changes which may include, but are not limited to functional ATR inhibition, ctDNA and CTCs.

Time frame: Biopsies of tumour at baseline and last day of dosing

Best objective response

Best objective response will be determined for each patient based on the best response recorded from start of study treatment to end of treatment, including any assessments for confirmation after the end of treatment using RECIST 1.1.

Time frame: From first dose to confirmed progressive disease (approximately 1 year)

Objective response rate

Objective response rate is defined as the percentage of patients who have at least one response of CR or PR prior to any evidence of progression (as defined by RECIST 1.1) that is confirmed at least 4 weeks later.

Time frame: From first dose to confirmed progressive disease (approximately 1 year)

Percentage change in tumour size

Percentage change in tumour size will be determined for patients with measurable disease at baseline and is derived at each visit by the percentage change from baseline in the sum of the diameters of TLs. The best percentage change in tumour size will be the patient's value representing the largest decrease (or smallest increase) from baseline in tumour size using RECIST 1.1.

Time frame: From first dose to confirmed progressive disease (approximately 1 year)

Durable response rate

Duration of response will be defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint using RECIST 1.1.

Time frame: From first documented response to confirmed progressive disease (approximately 1 year)

Progression free survival

Progression free survival (PFS) is defined as the time from start of treatment (first dose of ceralasertib) until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from therapy or receives another anti-cancer therapy prior to progression using RECIST 1.1.

Time frame: From first dose to confirmed progressive disease (approximately 1 year)

Survival assessment /status

Module 2 only. To be obtained for all patients who received ceralasertib and olaparib in part A2, B1, B2, B3, B4 and B5.

Time frame: From first dose to confirmed progressive disease (approximately 1 year)

Module 4: Safety and tolerability in terms of AE and SAE as recorded in safety measures

Safety measures: AEs assessments (CTCAE grading)

Time frame: 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

Module 4 only: Effect of food on ceralasertib absorption by Cmax in a fasted and fed state (Part A)

Intensive PK sampling at defined timepoints to measure geometric mean and 90% CI for the ratio of fed: fasted in Cmax - Maximum plasma concentration (Cmax)