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

AstraZeneca

Status and phase: Active, not recruiting; Phase 2

Conditions: Advanced Solid Tumours

Treatments: Drug: Ceralasertib

Study type: Interventional

Funder types: Industry

Identifiers

NCT04564027

2020-002529-27 (EudraCT Number)

D5339C00001

Details and patient eligibility

About

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

Full 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.

Enrollment: 54 patients

Sex: All

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

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:

  1. Unstable angina pectoris.
  2. Congestive heart failure > Class 2 as defined by the New York Heart Association
  3. Acute myocardial infarction.
  4. Significant ventricular or supraventricular arrhythmias.
  5. Mean resting corrected QT interval (QTc) > 470 msec obtained from three electrocardiograms (ECGs) in 24 hours using the Fredericia formula.
  6. 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.
  7. 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

---

54 participants in 2 patient groups

Cohort A

Experimental group

Description:

Eligible participants (ATM altered AST), will receive oral dose of Ceralasertib as monotherapy.

Treatment:

Drug: Ceralasertib

Cohort B

Experimental group

Description:

Eligible participants (ATM altered mCRPC), will receive oral dose of Ceralasertib as monotherapy.

Treatment:

Drug: Ceralasertib