A Study Investigating DNA-damage Response Agents in Molecularly Altered Advanced Cancer
Study Details
Study Description
Brief Summary
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort A Eligible participants (ATM altered AST), will receive oral dose of Ceralasertib as monotherapy. |
Drug: Ceralasertib
Tablets will be administered orally
Other Names:
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| Experimental: Cohort B Eligible participants (ATM altered mCRPC), will receive oral dose of Ceralasertib as monotherapy. |
Drug: Ceralasertib
Tablets will be administered orally
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Cohort A: Objective response rate (ORR) by response evaluation ceiteria in solid tumours (RECIST) version 1.1 [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort B: Composite response rate by RECIST version 1.1 [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
Secondary Outcome Measures
- Cohort A: Duration of Radiological response (DoR) by RECIST version 1.1 [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort A: Progression free survival (PFS) by RECIST version 1.1 [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort B: ORR by RECIST version 1.1 [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort B: Proportion of participants with confirmed CTC count conversion from unfavourable to favourable [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort B: Proportion of participants with confirmed prostate specific antigen (PSA) decline ≥ 50% [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
Proportion of participants with a PSA decline of ≥ 50% confirmed by a second consecutive measurement at least 3 weeks later.
- Cohort B: Radiological progression free survival (rPFS) by RECIST 1.1 [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
rPFS is defined as the time from the start of treatment until the date of objective radiographic disease progression or death.
- Cohort B: Duration of radiological response. [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort A and Cohort B: Best percentage change in tumour size [From Screening (Day -28 to -1) until disease progression or withdrawal of consent (upto approximately 3 years)]
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.
- Cohort A and B: Number of participants with serious and non-serious adverse events [From Screening (Day -28 to Day -1) until Safety follow-up (30 days after last dose) (upto approximately 3 years)]
To assess the safety and tolerability profile of ceralasertib.
Eligibility Criteria
Criteria
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.
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Participant must have normal organ and bone marrow function measured within 28 days prior to the first dose of study intervention.
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Participants who have no curative treatment options and are deemed appropriate for an investigational study in the opinion of the investigator.
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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.
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Previously received and progressed on at least one novel hormonal agent (eg, abiraterone acetate, apalutamide, and/or enzalutamide) for the treatment of prostate cancer
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Participants with histologically confirmed metastatic castrate resistant prostate cancer.
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Documented prostate cancer progression at study entry while on androgen deprivation or after bilateral orchiectomy as assessed by the investigator.
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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:
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Unstable angina pectoris.
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Congestive heart failure > Class 2 as defined by the New York Heart Association
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Acute myocardial infarction.
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Significant ventricular or supraventricular arrhythmias.
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Mean resting corrected QT interval (QTc) > 470 msec obtained from three electrocardiograms (ECGs) in 24 hours using the Fredericia formula.
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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.
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For Cohort B (mCRPC]), surgery or local prostatic intervention (excluding a prostatic biopsy) within 28 days of Cycle 1 Day 1.
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Participants with known active infections ((i.e., hepatitis B or C, tuberculosis, or COVID-19).
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Participants considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection.
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Participants with symptomatic and/or uncontrolled brain metastases.
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Previous therapy with an telangiectasia and rad3 related protein inhibitor.
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Exposure to a small molecule investigational product within 14 days or 5 half-lives.
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Concomitant use of known strong CYP 3A inhibitors and inducers.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Tucson | Arizona | United States | 85719 |
| 2 | Research Site | Beverly Hills | California | United States | 90211 |
| 3 | Research Site | Duarte | California | United States | 91010 |
| 4 | Research Site | La Jolla | California | United States | 92093 |
| 5 | Research Site | Los Angeles | California | United States | 90089 |
| 6 | Research Site | Sacramento | California | United States | 95817 |
| 7 | Research Site | San Francisco | California | United States | 94115 |
| 8 | Research Site | Tampa | Florida | United States | 33612 |
| 9 | Research Site | Indianapolis | Indiana | United States | 46202 |
| 10 | Research Site | New Orleans | Louisiana | United States | 70056 |
| 11 | Research Site | Baltimore | Maryland | United States | 21231 |
| 12 | Research Site | Boston | Massachusetts | United States | 02215 |
| 13 | Research Site | Ann Arbor | Michigan | United States | 48109 |
| 14 | Research Site | Saint Paul | Minnesota | United States | 55102 |
| 15 | Research Site | Las Vegas | Nevada | United States | 89119 |
| 16 | Research Site | New York | New York | United States | 10065 |
| 17 | Research Site | Syracuse | New York | United States | 13210 |
| 18 | Research Site | Ephrata | Pennsylvania | United States | 17522 |
| 19 | Research Site | Philadelphia | Pennsylvania | United States | 19104 |
| 20 | Research Site | Myrtle Beach | South Carolina | United States | 29572 |
| 21 | Research Site | Bordeaux | France | 33076 | |
| 22 | Research Site | Dijon | France | 21079 | |
| 23 | Research Site | Lyon | France | 69373 | |
| 24 | Research Site | Poitiers Cedex | France | 86021 | |
| 25 | Research Site | Vandoeuvre les Nancy | France | 54519 | |
| 26 | Research Site | Barcelona | Spain | 08036 | |
| 27 | Research Site | Barcelona | Spain | 08907 | |
| 28 | Research Site | Barcelona | Spain | 8035 | |
| 29 | Research Site | Cáceres | Spain | 10003 | |
| 30 | Research Site | Madrid | Spain | 28034 | |
| 31 | Research Site | Madrid | Spain | 28041 | |
| 32 | Research Site | Madrid | Spain | 28050 |
Sponsors and Collaborators
- AstraZeneca
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D5339C00001