A Study Investigating DNA-damage Response Agents in Molecularly Altered Advanced Cancer

Study Overview
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Brief Summary
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The study is investigating efficacy, safety and tolerability of DNA-damage Response Agents (or Combinations), in participants with advanced/metastatic solid malignancies whose tumours contain molecular alterations

Detailed Description
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Current module of the study will consist of 2 cohorts as follows: Cohort A (Advanced Solid Tumours [AST]): A total of  25 molecularly eligible and centrally confirmed participants dosed at ceralasertib 160 mg twice daily will be enrolled into this cohort. Cohort B (Metastatic castration-resistant prostate cancer [mCRPC]): A total of  27 molecularly eligible and centrally confirmed participants dosed at ceralasertib 160 mg twice daily will be enrolled into Cohort B. Unfavourable circulating tumour cells (CTC) count requirement may be introduced for all participants to ensure an adequate (approximately ≥ 50%) number of participants with CTC count ≥ 5/7.5 mL blood. The screening will have 2 parts, Part 1 and Part 2, which apply for both Cohort A and Cohort B.

Official Title
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A Modular Phase 2a Multicentre Open-Label Study to Investigate DNA-damage Response Agents (or Combinations) in Patients With Advanced Cancer Whose Tumours Contain Molecular Alterations (PLANETTE)

Conditions
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Advanced Solid Tumours

Intervention / Treatment
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* Drug: Ceralasertib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a histologically confirmed diagnosis of AST (excluding NSCLC) or mCRPC tumour. Participants must have a deleterious or suspected deleterious ATM mutation in tumour or blood (germline or ctDNA). Definitions of qualifying ATM mutations may include deleterious/suspected deleterious, pathogenic/likely pathogenic, disease- or cancer-associated variants, or equivalent wording. Variants of unknown significance, benign or likely benign alterations are not qualifying. Participant must have normal organ and bone marrow function measured within 28 days prior to the first dose of study intervention. Participants who have no curative treatment options and are deemed appropriate for an investigational study in the opinion of the investigator. Availability of archival or fresh tumour specimens for central testing of ATM protein loss using immunohistochemistry and for confirmation of ATM mutation using next generation sequencing. Previously received and progressed on at least one novel hormonal agent (eg, abiraterone acetate, apalutamide, and/or enzalutamide) for the treatment of prostate cancer Participants with histologically confirmed metastatic castrate resistant prostate cancer. Documented prostate cancer progression at study entry while on androgen deprivation or after bilateral orchiectomy as assessed by the investigator. Serum testosterone levels ≤ 50 ng/dL (≤ 1.75 nmol/L) within (≤) 28 days before enrolment. Exclusion Criteria: Any of the following cardiac diseases currently or within the last 6 months: Unstable angina pectoris. Congestive heart failure > Class 2 as defined by the New York Heart Association Acute myocardial infarction. Significant ventricular or supraventricular arrhythmias. Mean resting corrected QT interval (QTc) > 470 msec obtained from three electrocardiograms (ECGs) in 24 hours using the Fredericia formula. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome or unexplained sudden death under 40 years of age. For Cohort B (mCRPC]), surgery or local prostatic intervention (excluding a prostatic biopsy) within 28 days of Cycle 1 Day 1. Participants with known active infections ((i.e., hepatitis B or C, tuberculosis, or COVID-19). Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Participants with symptomatic and/or uncontrolled brain metastases. Previous therapy with an telangiectasia and rad3 related protein inhibitor. Exposure to a small molecule investigational product within 14 days or 5 half-lives. Concomitant use of known strong CYP 3A inhibitors and inducers.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>Eligible participants (ATM altered AST), will receive oral dose of Ceralasertib as monotherapy. | Drug: Ceralasertib<br>* Tablets will be administered orally<br>* Other names: AZD6738;|
| Experimental: Cohort B<br>Eligible participants (ATM altered mCRPC), will receive oral dose of Ceralasertib as monotherapy. | Drug: Ceralasertib<br>* Tablets will be administered orally<br>* Other names: AZD6738;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Objective response rate (ORR) by response evaluation ceiteria in solid tumours (RECIST) version 1.1 | ORR is defined as the percentage of participants who have at least one response of complete response (CR) or partial response (PR) prior to any evidence of progression (as defined by response evaluation criteria in solid tumours [RECIST] 1.1) that is confirmed at least 4 weeks later. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort B: Composite response rate by RECIST version 1.1 | Composite response rate is defined as the investigator assessed radiological response by RECIST 1.1 for soft tissue and visceral lesions and prostate cancer working group 3 (PCWG3) for bone lesions, prostate specific antigen (PSA) decline, and/or circulating tumour cell [CTC] conversion. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort A: Duration of Radiological response (DoR) by RECIST version 1.1 | DoR is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort A: Progression free survival (PFS) by RECIST version 1.1 | PFS is defined as the time from start of study intervention until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy prior to progression. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort B: ORR by RECIST version 1.1 | Radiological ORR is defined as the percentage of participants with a confirmed response of CR or PR in their soft tissue and visceral lesions assessed by RECIST 1.1 in the absence of bone progression assessed by PCWG3. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort B: Proportion of participants with confirmed CTC count conversion from unfavourable to favourable | Conversion of CTC count is defined as a conversion from unfavourable at baseline (≥ 5/7.5 mL blood) to favourable post-baseline (< 5/7.5 mL blood). The percentage of participants with CTC count conversion based on those with unfavourable CTC at baseline, will be presented for this study. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort B: Proportion of participants with confirmed prostate specific antigen (PSA) decline ≥ 50% | Proportion of participants with a PSA decline of ≥ 50% confirmed by a second consecutive measurement at least 3 weeks later. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort B: Radiological progression free survival (rPFS) by RECIST 1.1 | rPFS is defined as the time from the start of treatment until the date of objective radiographic disease progression or death. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort B: Duration of radiological response. | DoR is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort A and Cohort B: Best percentage change in tumour size | Change in tumour size will be determined. Best percentage change in tumour size is defined as the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction in the sum of the longest diameters (or the short axis measurements for lymph nodes) of the target lesions. | From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years) | 
| Cohort A and B: Number of participants with serious and non-serious adverse events | To assess the safety and tolerability profile of ceralasertib. | From Screening (Day -28 to Day -1) until Safety follow-up (30 days after last dose) (upto approximately 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ataxia telangiectasia mutated, Metastatic castration-resistant prostate cancer, Rad3-related protein