Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer
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|ClinicalTrials.gov Identifier: NCT02630199|
Recruitment Status : Recruiting
First Posted : December 15, 2015
Last Update Posted : May 20, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Refractory Cancer||Drug: AZD6738 Drug: Paclitaxel||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||21 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I, Open-Label Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer|
|Actual Study Start Date :||December 2015|
|Estimated Primary Completion Date :||December 2019|
|Estimated Study Completion Date :||December 2020|
Experimental: AZD6738 + paclitaxel
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.
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.
Paclitaxel 80mg/m2 on days 1,8, and 15 every 4 weeks
- Number of participants With Abnormal Laboratory Values and/or Adverse Events to assess Safety and tolerability of AZD6738. [ Time Frame: 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. [ Time Frame: Up to 6 months ]
- Objective Response rate [ Time Frame: expected average of 1 years ]
- Overall survival (OS) [ Time Frame: expected average of 1 years ]
- progression-free survival (PFS) [ Time Frame: expected average of 1 years ]
- Area under the plasma concentration versus time curve (AUC) after single and multiple dose [ Time Frame: Day 0 and Day 1 ]
- Peak Plasma Concentration (Cmax) [ Time Frame: Day 0 and Day 1 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02630199
|Contact: Jeeyun Lee, MD,Ph.D.||2-3410-3459 ext firstname.lastname@example.org|
|Korea, Republic of|
|Samsung Medical Center||Recruiting|
|Seoul, Korea, Korea, Republic of, 135-720|
|Contact: yoon jeong ahn 82-2-2148-7395|
|Principal Investigator: Jeeyun Lee, MD, PhD|