Clinical Trials /

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

NCT02264678

Description:

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

Related Conditions:
  • Breast Carcinoma
  • Fallopian Tube Carcinoma
  • Gastric Adenocarcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: D5330C00004
  • NCT ID: NCT02264678

Conditions

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

Interventions

DrugSynonymsArms
Administration of ceralasertib in combination with carboplatinModule 1 Part A
Administration of ceralasertibModule 2 Part A1
Administration of ceralasertib in combination with olaparibModule 2 Part A2
Administation of ceralasertib in combination with durvalumabModule 3 Part A

Purpose

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.

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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Module 1 Part AExperimentalModule 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).
  • Administration of ceralasertib in combination with carboplatin
Module 1 Part BExperimentalModule 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.
  • Administration of ceralasertib in combination with carboplatin
Module 2 Part A1ExperimentalModule 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.
  • Administration of ceralasertib
Module 2 Part A2ExperimentalModule 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.
  • Administration of ceralasertib in combination with olaparib
Module 2 Part B1ExperimentalModule 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.
  • Administration of ceralasertib in combination with olaparib
Module 2 Part B2ExperimentalModule 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.
  • Administration of ceralasertib in combination with olaparib
Module 2 Part B3ExperimentalModule 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.
  • Administration of ceralasertib in combination with olaparib
Module 2 Part B4ExperimentalModule 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.
  • Administration of ceralasertib in combination with olaparib
Module 3 Part AExperimentalModule 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.
  • Administation of ceralasertib in combination with durvalumab
Module 3 Part BExperimentalModule 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.
  • Administation of ceralasertib in combination with durvalumab
Module 2 Part B5ExperimentalPatients with BRCA mutant (either germline or somatic) 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 a dose, frequency and schedule recommended from Module 2 Part A2.
  • Administration of ceralasertib in combination with olaparib

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 1 and 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 1 Part B Study expansion: second line lung adenocarcinoma with ATM deficient
             tumours.

          -  Module 2 Part B All - 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

          -  Module2 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: BRCA mutant ovarian cancer patient who are Platinum
             sensitive and have previously progressed on a PARPi Module 3: advanced recurrent or
             metastatic non-small cell lung cancer, or head and neck squamous cell carcinoma

        Principal exclusion criteria

          -  A diagnosis of ataxia telangiectasia

          -  Prior exposure to an ATR inhibitor

          -  Bad reaction to ceralasertib

          -  Module 1: Contra-indicated for treatment with carboplatin

          -  Module 2: Contra-indicated for treatment with olaparib

          -  Module 3: Contra-indicated for treatment with durvalumab
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability in terms of AE and SAE (including death), as recorded in safety measures.
Time Frame:From baseline until 28 days after discontinuation of study treatment for Module 1 and 2 or until 90 days after discontinuation of study treatment for Module 3
Safety Issue:
Description:Safety measures include AEs, SAEs, ECG, physical examination, pulse, blood pressure, body temperature, weight and laboratory variables

Secondary Outcome Measures

Measure:Maximum Observed Plasma Concentration (Cmax) of ceralasertib
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)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Cmax.
Measure:Time to observed Cmax (Tmax) for ceralasertib
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)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive Tmax.
Measure:Area under the plasma concentration-time curve (AUC) for ceralasertib
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)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of ceralasertib at a series of time points to derive AUC.
Measure:Maximum Observed Plasma Concentration (Cmax) of Carboplatin
Time Frame:At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Cmax.
Measure:Time to observed Cmax (Tmax) for Carboplatin
Time Frame:At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive Tmax.
Measure:Area under the plasma concentration-time curve (AUC) for Carboplatin
Time Frame:At predefined intervals throughout the Carboplatin treatment period (approximately 4 weeks for Module 1)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of Carboplatin at a series of time points to derive AUC.
Measure:Maximum Observed Plasma Concentration (Cmax) of Olaparib
Time Frame:At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Cmax.
Measure:Time to observed Cmax (Tmax) for Olaparib
Time Frame:At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive Tmax.
Measure:Area under the plasma concentration-time curve (AUC) for Olaparib
Time Frame:At predefined intervals throughout the Olaparib treatment period (approximately 12 weeks for Module 2)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of Olaparib at a series of time points to derive AUC.
Measure:Maximum Observed Plasma Concentration (Cmax) of durvalumab
Time Frame:At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Cmax.
Measure:Time to observed Cmax (Tmax) for durvalumab
Time Frame:At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive Tmax.
Measure:Area under the plasma concentration-time curve (AUC) for durvalumab
Time Frame:At predefined intervals throughout the durvalumab treatment period (approximately 28 weeks + 90days post IP disc. for Module 3)
Safety Issue:
Description:Blood samples will be collected to assess plasma concentration of durvalumab at a series of time points to derive AUC.
Measure:Assessment of pharmacodynamic biomarker changes
Time Frame:Biopsies of tumour at baseline, last day of dosing and following progression of disease
Safety Issue:
Description: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.
Measure:Best objective response
Time Frame:At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study
Safety Issue:
Description:To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1), olaparib (module 2) and durvulamab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure:Objective response rate
Time Frame:At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study
Safety Issue:
Description:To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure:Percentage change in tumour size
Time Frame:At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study
Safety Issue:
Description:To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure:Durable response rate
Time Frame:At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study
Safety Issue:
Description:To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure:Progression free survival
Time Frame:At baseline and every 6 weeks (module 1) and every 8 weeks (module 2 & 3) until disease progression or withdrawal from study
Safety Issue:
Description:To obtain a preliminary assessment of the anti-tumour activity of the combination of ceralasertib and carboplatin (module 1) and olaparib (module 2) and durvalumab (module 3) by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1
Measure:Survival assessment /status
Time Frame:Every 8 weeks (+/- 1 week) after objective disease progression
Safety Issue:
Description:Module 2 only. To be obtained for all patients with gastric adenocarcinoma who received ceralasertib and olaparib in part A2, B1, B2, B3 and B4

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • ATM deficient, ATM proficient, HER2 negative, Breast, Gastric, Head & Neck, Lung, Ovarian

Last Updated

June 15, 2020