Refractory CancerPhase 1NCT02630199
Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer
A Phase 1 study testing AZD6738 and Paclitaxel in people with Refractory Cancer, run by Samsung Medical Center at 1 site in South Korea.
Trial 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. Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Refractory Cancer
- What is being tested?
- AZD6738 and Paclitaxel
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 65 participants
- Where
- 1 siteSouth Korea
- Study dates
- Dec 2015to 19 Apr 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- Provision of tumor sample (from either a resection or biopsy): however this criteria is optional for this study (i.e. if no biopsy sample available, not an exclusion criteria).
- 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
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- 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.
Who cannot join
- 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.
- Treatment with any investigational product during the last 14 days before the enrollment (or a longer period depending on the defined characteristics of the agents used).
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- Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 3 weeks from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment.
- - Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
- Receiving, or having received, concomitant medications, herbal supplements and/or foods that significantly modulate CYP3A4 or Pgp activity (wash out periods of two weeks, but three weeks for St. John's Wort). Note these include common azole antifungals, macrolide antibiotics and other medications listed in Appendix I.
- With the exception of alopecia, any ongoing toxicities (>CTCAE grade 1) caused by previous cancer therapy.
- Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks before the enrollment.
- Resting ECG with measurable QTcF > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
- Patients with cardiac problem as follows: uncontrolled hypertension or hypotension (BP ≥150/95 mmHg despite medical therapy, BP <100/60 mmHg or orthostatic hypotension fall in BP >20 mmHg) Left ventricular ejection fraction <55% measured by echocardiography, Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest , Symptomatic heart failure (NYHA grade II-IV), Prior or current cardiomyopathy, Severe valvular heart disease, Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical therapy), Acute coronary syndrome within 6 months prior to starting treatment
- Female patients who are breast-feeding or child-bearing
- Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus (HIV)
- A diagnosis of ataxia telangiectasia
- Inadequate bone marrow and impaired hepatic or renal function as demonstrated by any of the following laboratory values:
- Haemoglobin < 9.0 g/dL (transfusion allowed)
- Absolute neutrophil count (ANC) <1.5 x 109/L
- White blood cells (WBC) ≤ 3 x 109/L
- Platelet count < 100 x 109/L (transfusion allowed)
- Albumin < 33g/L
- Total bilirubin < 1.5 x institutional upper limit of normal (ULN)
- AST (SGOT)/ALT (SGPT) > 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be > 5x ULN
- Serum creatinine > 1.5 x institutional ULN
- Glomerular filtration rate (GFR) < 45 mL/min, as assessed using the standard methodology at the investigating centre (i.e. cockcroft-Gault, MDRD or CKD-EPI formulae, EDTA clearance or 24 h urine collection)
- Haematuria: +++ on microscopy or dipstick
- INR ≥ 1.5 or other evidence of impaired hepatic synthesis function
- Previous allogenic bone marrow transplant
- Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I, Open-Label Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer
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.
Read more
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
- Being tested
- AZD6738, Paclitaxel
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD6738Drug
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.
PaclitaxelDrug
Paclitaxel 80mg/m2 on days 1,8, and 15 every 4 weeks
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: AZD6738; Drug: Paclitaxel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of participants With Abnormal Laboratory Values and/or Adverse Events to assess Safety and tolerability of AZD6738.
Measured: 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.
Measured: Up to 6 months
Secondary outcomes (5)
Objective Response rate
Measured: expected average of 1 years
Overall survival (OS)
Measured: expected average of 1 years
progression-free survival (PFS)
Measured: expected average of 1 years
Area under the plasma concentration versus time curve (AUC) after single and multiple dose
Measured: Day 0 and Day 1
Peak Plasma Concentration (Cmax)
Measured: Day 0 and Day 1
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2015 (estimated)
- Study startDec 2015
- Primary completionDec 2020
- Study completion19 Apr 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Refractory CancerStudies of the same condition, open and under way.
- More trials run by Samsung Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- Samsung Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jeeyun Lee, Samsung Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02630199
- Sponsor's protocol ID
- 2015-10-038
- Status last verified
- Jun 2022
- First submitted
- 6 Dec 2015
- Last updated
- 15 Jun 2022
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I, Open-Label Study of AZD6738, DNA Damage Repair/Novel Anti-cancer Agent, in Combination With Paclitaxel, in Refractory Cancer
- ClinicalTrials.gov ID
- NCT02630199
- Acronym / sponsor ID
- 2015-10-038
- Conditions
- Refractory Cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- Samsung Medical CenterUniversity, hospital or other
- Study start
- Dec 2015 (actual)
- Primary completion
- Dec 2020 (actual)
- Study completion
- 19 Apr 2021 (actual)
- First posted
- 15 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AZD6738 + paclitaxel | Experimental | Drug: AZD6738, Drug: PaclitaxelThe 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. |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- 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.
- Provision of tumor sample (from either a resection or biopsy): however this criteria is optional for this study (i.e. if no biopsy sample available, not an exclusion criteria).
- 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.
Key exclusion criteria (30 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD6738The 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. | Drug | AZD6738 + paclitaxel |
| PaclitaxelPaclitaxel 80mg/m2 on days 1,8, and 15 every 4 weeks | Drug | AZD6738 + paclitaxel |
Primary outcome
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
5 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jun 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing AZD6738 and Paclitaxel in people with Refractory Cancer, run by Samsung Medical Center at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2022.