Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer

NCT02630199 | Completed Phase 1 DMC

• 1 other identifier: 2015-10-038
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a single center open label phase I study of AZD6738, DNA damage repair/novel cancer agent, in combination with paclitaxel in metastatic cancer patients who have failed standard chemotherapy. AZD6738 is an orally dosed selective and potent inhibitor of Ataxia Telangiectasis and Rad3 Related (ATR) kinase with good selectivity against other Pi3 kinase family members. ATR is a serine/threonine protein kinase and member of the phosphatidylinositol 3-kinase related kinase (PIKK) family. During normal replication, ATR is recruited at stalled replication forks which can progress to double strand breaks if left unrepaired. ATR is also recruited to single strand DNA coated with Replication Protein A (RPA) following single strand DNA damage or the resection of double strand breaks. Recruitment and activation of ATR leads to cell cycle arrest in the S phase while the DNA is repaired and the stalled replication fork resolved, or nuclear fragmentation and entry into programmed cell death (apoptosis). In the clinic ATR inhibitors are expected to cause growth inhibition in tumour cells dependent upon ATR for DNA repair e.g. ATM-deficient tumours. In addition to monotherapy activity, ATR inhibitors are also predicted to potentiate the activity of cytotoxic DNA damaging agents and radiotherapy (through inhibition of ATR-dependent DNA repair processes) when used in combination. While significant enhancement of anti-tumour activity may be achieved, data with AZD6738 suggest the potential need to reduce the ATR inhibitor dose and intensity (relative to monotherapy dose) and introduce dosing breaks to allow normal tissue recovery when used in combination with systemic DNA damaging chemotherapy agents, in order to maintain tolerable therapeutic margins. The mechanism of action of AZD6738 suggests the potential to combine it with a number of anti-cancer treatments, resulting in either synergistic or additive activity. This study is evaluating the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD6738 at increasing doses, in combination with paclitaxel as one of standard salvage regimen in patients with advanced cancer. The study will consist of two parts, each evaluating the safety and tolerability of a specific combination agent, paclitaxel with different drug schedules. An oral formulation of AZD6738 will be used. The PART A will be in combination with paclitaxel; the starting dose of 40 mg AZD6738 OD will be escalated to reach a maximum tolerated dose in patients with advanced solid malignancies, as defined by dose-limiting toxicity. The PART B will be an independent parallel PK expansion cohort with cycle 0 of AZD6738 on D1, D8\~D21 monotherapy followed by combination therapy with weekly paclitaxel from cycle 1. Investigators will modify to recruit the minimum or maximum number of patients depending on data generated from other studies using AZD6738.

Conditions

Refractory Cancer

Outcome Measures

Primary Outcomes (2)

• Number of participants With Abnormal Laboratory Values and/or Adverse Events to assess Safety and tolerability of AZD6738.

  From baseline until 28 days after discontinuation of study treatment, assessed up to 12 months

• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 to determine maximal tolerate dose (MTD) of AZD6738.

  Up to 6 months

Secondary Outcomes (5)

• Objective Response rate

  expected average of 1 years

• Overall survival (OS)

  expected average of 1 years

• progression-free survival (PFS)

  expected average of 1 years

• Area under the plasma concentration versus time curve (AUC) after single and multiple dose

  Day 0 and Day 1

• Peak Plasma Concentration (Cmax)

  Day 0 and Day 1

Study Arms (1)

AZD6738 + paclitaxel

EXPERIMENTAL

The PART A will be in combination with paclitaxel; the starting dose of 40 mg AZD6738 OD will be escalated to reach a maximum tolerated dose in patients with advanced solid malignancies, as defined by dose-limiting toxicity. The PART B will be an independent parallel PK expansion cohort with cycle 0 of AZD6738 on D1, D8\~D21 monotherapy followed by combination therapy with weekly paclitaxel from cycle 1.

Drug: AZD6738; Drug: Paclitaxel

Interventions

AZD6738 DRUG

The starting dose of 40 mg AZD6738 OD will be escalated to reach a maximum tolerated dose in patients with advanced solid malignancies, as defined by dose-limiting toxicity.

AZD6738 + paclitaxel

Paclitaxel DRUG

Paclitaxel 80mg/m2 on days 1,8, and 15 every 4 weeks

AZD6738 + paclitaxel

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of fully informed consent prior to any study specific procedures.
• Patients must be \> 19 years of age.
• Refractory cancer patients who have failed to standard of care chemotherapy.

You may not qualify if:

• Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. Especially, patients must fast (water to drink only) from at least 2 hours prior to taking a dose to at least 1 hour post-dose for all doses.
• ECOG performance status 0-1
• Patients must have a life expectancy ≥ 3 months from proposed first dose date.
• At least one measurable lesion that can be accurately assessed by imaging at baseline and following up visits.
• Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment.
• Patients of child-bearing potential should be using adequate contraceptive measures (two forms of highly reliable methods) should not be breast feeding and must have a negative pregnancy test prior to start of dosing.or Patients must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
• Male patients must be willing to use barrier contraception for the duration of the study and:
• for one week after the last dose of study drug if the sexual partner is not of child bearing potential
• for 6 months after last dose of study drug and in combination with a highly reliable contraceptive method for sexual partners of child-bearing potential
• Male patients must be willing to not donate sperm for the duration of study or up to 6 months after the last dose of study drug.
• More than four prior chemotherapy regimens (excluding adjuvant chemotherapy) for cancer treatment
• Any previous treatment with ATR inhibitors (small molecules)
• Any previous treatment with paclitaxel (docetaxel is allowed if in physician's discretion, the tumor is not absolutely refractory to taxane)
• Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for ≤5 years.
• Patients unable to swallow orally administered medication.

Sponsors & Collaborators

• Samsung Medical Center: lead

Study Sites (1)

Samsung Medical Center

Seoul, Korea, 135-720, South Korea

Location

MeSH Terms

Conditions

Neoplasms

Interventions

ceralasertib; Paclitaxel

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD,PhD,Division of hematology-oncology,Department of medicine

Study Record Dates

• First Submitted: December 6, 2015
• First Posted: December 15, 2015
• Study Start: December 1, 2015
• Primary Completion: December 1, 2020
• Study Completion: April 19, 2021
• Last Updated: June 15, 2022

Record last verified: 2022-06

Locations

KR (1)