Primary objective:To evaluate the objective response rate (ORR) of AZD1775 in combination with gemcitabine, carboplatin, paclitaxel,or PLD in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancerSecondary…
ID
Source
Brief title
Condition
- Other condition
- Reproductive and genitourinary neoplasms gender unspecified NEC
- Ovarian and fallopian tube disorders
Synonym
Health condition
primaire buikvlieskanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this study is ORR for the arms included in the efficacy
assessment, defined as the proportion of patients achieving a complete or
partial tumour response according to Response Evaluation Criteria in Solid
Tumours (RECIST) v1.1 (Eisenhauer et al 2009).
Secondary outcome
1. DoR, defined as the time from first documented tumour response until the
date of documented progression or death from any cause
2.Treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and
deaths; clinically significant changes in safety-related laboratory parameters
according to National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI CTCAE v4.03) and abnormal vital signs.
3.DCR, defined as the proportion of patients achieving a complete response
(CR), partial response (PR), or stable disease (SD) according to RECIST v1.1
criteria.
4. GynaecologicCancer Intergroup (GCIG) CA-125 response, defined as the
proportion of patients achieving a 50% reduction in CA-125 levels from
baseline, if baseline level is *2 x the upper limit of normal (ULN) within 2
weeks prior to starting treatment. Response must be confirmed and maintained
for at least 28cdays
5.Plasma PK parameters of AZD1775 plus carboplatin, AZD1775 plus
paclitaxel,AZD1775 plus PLD, and AZD1775 plus gemcitabine
6.Plasma PK parameters of AZD1775 plus carboplatin, AZD1775 plus
paclitaxel,AZD1775 plus gemcitabine,and AZD1775 plus PLD
Background summary
This study is intended to understand the dose, dosage regimen, safety and
tolerability of AZD1775 in combination with various chemotherapy agents and to
assess its efficacy.The research hypothesis for the AZD1775 drug development
programme is that administration of AZD1775 combined with chemotherapy in women
with platinumresistant ovarian, fallopian tube, or primary peritoneal carcinoma
experience improved progression-free survivalcompared to women receiving
chemotherapy alone. This study is being conducted to understand the dose
level, dosing schedule, safety, and tolerability of AZD1775 combined with
chemotherapy agents such that they can be subsequently studied for improvement
in efficacy.
Study objective
Primary objective:
To evaluate the objective response rate (ORR) of AZD1775 in combination with
gemcitabine, carboplatin, paclitaxel,or PLD in patients with platinum-resistant
epithelial ovarian, fallopian tube, or primary peritoneal cancer
Secondary Objectives:
1.To evaluate the duration of response (DoR) of AZD1775 in combination with
gemcitabine, carboplatin,paclitaxel, or PLD
2.To evaluate the safety and tolerability of AZD1775 in combination with
paclitaxel, gemcitabine, carboplatin or PLD in patients with platinum-resistant
epithelial ovarian, fallopian tube, or primary peritoneal cancer
3.To evaluate the disease control rate (DCR) of AZD1775 in combination with
carboplatin, paclitaxel,gemcitabine, or PLD in patients with platinum-resistant
epithelial ovarian, fallopian tube, or primary peritoneal cancer
4.To evaluate the Cancer Antigen-125 (CA-125) response of AZD1775 in
combination with carboplatin, paclitaxel,gemcitabine, or PLD in patients with
platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal
cancer.
5.To characterise the pharmacokinetics(PK)of AZD1775 plus carboplatin, AZD1775
plus paclitaxel, AZD1775 plus PLD, and AZD1775 plus gemcitabine
6.To assess the drug interaction between AZD1775 plus carboplatin, AZD1775 plus
paclitaxel, AZD1775 plus gemcitabine, and AZD1775 plus PLD
Exploratory Objectives:
1. To identify genetic alterations in breast cancer genes 1 and 2 (BRCA1and
BRCA2) and other relevant genes,including TP53,from analysis of archived or
fresh tumour tissue collected at baseline, and to determine if the presence of
a genetic alteration is predictive of clinical outcomes.
Molecular
2. To analyse changes in plasma circulating free tumour DNA (cfDNA) over time,
from baseline, to restaging, and at disease progression. (This exploratory
analysis will be reported separately from the Clinical Study Report [CSR].)
Blood
3. To obtain preliminary estimates of the overall survival (OS) and
progression-free survival (PFS) of AZD1775 in combination with gemcitabine,
paclitaxel,carboplatin, or PLD.
4.To collect and store deoxyribonucleic acid (DNA) for future research into
genes/genetic variations that may influence PK orresponse to AZD1775 (i.e.,
absorption, distribution, metabolism, excretion, safety and efficacy) and/or
susceptibility to the development of cancers.
Study design
This is an open-label, four-arm lead-in safety and efficacy study in which
AZD1775 will be combined in four separate treatment arms as follows: AZD1775
plus gemcitabine(Arm A); AZD1775 plus weekly paclitaxel(Arm B); AZD1775 plus
carboplatin (Arm C); and AZD1775 plus PLD (Arm D). A subset of patients will be
evaluated for the safety assessment of each treatment arm (see Section 7.2.3.1
protocol).
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional
patients at selected sites as part of a further efficacy evaluation based on
emerging data that suggests clinical activity. The AZD1775 plus carboplatin arm
(Arm C) will enrol approximately 23 patients overall at selected sites as part
of a further efficacy evaluation based on emerging data that suggests clinical
activity. To further optimise the dosing schedule of AZD1775 in Arm C, a safety
expansion arm (referred to as Arm C2) of approximately 12 additional patients
will be enrolled at selected sites to receive carboplatin AUC 5 IV on Day 1 of
a 21 day cycle in combination with AZD1775 BID for 2.5 days per dosing week
(QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2
(D8-10) (2 weeks on followed by 1 week off). These additional weeks of AZD1775
dosing are meant to explore emerging pre-clinical and clinical data that
suggest that prolonged AZD1775 exposure may increase the clinical activity.
Initially, 6 patients will be enrolled in a 3-weekly AZD1775 dosing cycle; if 1
patient or less experiences a DLT during Cycle 1, then an additional 6 patients
will be enrolled for a total of 12 patients. However, if 2 or more of the
first 6 patients experience a DLT then the AZD1775 dosing may be modified to 2
weeks on followed by 1 week off. All decisions which include but are not
limited to cohort dosing, dose escalation or de-escalation will be reviewed by
the Safety Review Team (SRT). Modified PK assessments will be obtained to
harmonise and accommodate the investigation of alternative dose levels and/or
schedules.
Intervention
This is an open-label, four-arm lead-in safety and efficacy study in which
AZD1775 will be combined in four separate treatment arms as follows: AZD1775
plus gemcitabine(Arm A); AZD1775 plus weekly paclitaxel(Arm B); AZD1775 plus
carboplatin (Arm C); and AZD1775 plus PLD (Arm D). A subset of patients will be
evaluated for the safety assessment of each treatment arm (see Section 7.2.3.1
protocol).
The AZD1775 plus paclitaxel arm (Arm B) will enrol approximately 30 additional
patients at selected sites as part of a further efficacy evaluation based on
emerging data that suggests clinical activity. The AZD1775 plus carboplatin arm
(Arm C) will enrol approximately 23 patients overall at selected sites as part
of a further efficacy evaluation based on emerging data that suggests clinical
activity. To further optimise the dosing schedule of AZD1775 in Arm C, a safety
expansion arm (referred to as Arm C2) of approximately 12 additional patients
will be enrolled at selected sites to receive carboplatin AUC 5 IV on Day 1 of
a 21 day cycle in combination with AZD1775 BID for 2.5 days per dosing week
(QW), on Weeks 1 (D1-3), 2 (D8-10) and 3 (D15-17), or on Weeks 1 (D1-3) and 2
(D8-10) (2 weeks on followed by 1 week off).
Study burden and risks
For all details, please refer to study schedule on page 44-55 of the protocol
(version 8, 19Jun2017). Also, see E4, E6, E9 for burden and possible risks.
Karlebyhus, Astraallen n.v.t.
Södertälje S-151 85
SE
Karlebyhus, Astraallen n.v.t.
Södertälje S-151 85
SE
Listed location countries
Age
Inclusion criteria
1. Has read and understands the informed consent form (ICF) and has given written consent.;2. Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal cancer.;3. Progressed within 6 months of completing at least 4 cycles of a first-line platinum-containing regimen for Stage III/IV disease. Patients with refractory disease (progression during platinum-containing therapy) are ineligible.;4. No more than 2-4 prior treatment regimens for Stage III/IV disease, defined as investigational, chemotherapy, hormonal, biologic, or targeted therapy.;5. Prior doxorubicin (or other anthracycline) at a cumulative dose of * 360 mg/m² or cumulative epirubicin dose of * 720 mg/m² (calculated using doxorubicin equivalent doses: 1 mg of doxorubicin <= 1 mg PLD <= 0.3 mg mitoxantrone <= 0.25 mg idarubicin). Subjects without any prior anthracycline exposure can also be included (applies to Arm D only).;6. At least 1 measurable lesion according to RECIST v1.1.;7. Any prior palliative radiation therapy must be completed at least 7 days prior to start of study treatment and patients must have recovered from any acute adverse effects prior to start of study treatment. ;8. ECOG Performance Status (PS) score of 0 - 1.;9. Baseline Laboratory Values within 7 days of starting study drugs:
a) ANC *1500/*L
b) HgB * 9 g/dL with no blood transfusions in the past 28 days
c) Platelets * 100,000/*L
d) ALT & AST * 3 x ULN or * 5 x ULN if known hepatic metastases
e) Serum bilirubin within normal limits (WNL) or *1.5 x ULN in patients with liver metastases; or total bilirubin * 3.0 x ULN with direct bilirubin WNL in patients with well documented Gilbert*s Syndrome.
f) Serum creatinine *1.5 x ULN OR measured creatinine clearance (CrCl) * 45 mL/min by the Cockcroft-Gault method.;10. Left ventricular ejection fraction (LVEF) WNL of the institution, as determined by multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm D only).;11. Female patients who are not of childbearing potential and fertile female patients of
childbearing potential who agree to use adequate contraceptive measures from 2
weeks prior to the study and until 1 month after study treatment discontinuation,
who are not breastfeeding, and who have a negative serum or urine pregnancy test
within 3 days prior to start of study treatment;12. Predicted life expectancy * 12 weeks;13. Must be *18 years of age.;14. Willingness and ability to comply with study and follow-up procedures.
Exclusion criteria
1. Participation in another clinical investigational study within the previous 28 days. ;2. Use of a study drug (approved or investigational drug therapy) * 21 days or 5 half-lives
(whichever is shorter) prior to the first dose of study treatment. For study drugs for which 5 half-lives is * 21 days, a minimum of 10 days between termination of the study drug and administration of study treatment is required.;3. Major surgical procedures * 28 days of beginning study treatment, or minor surgical
procedures * 7 days. No waiting required following port-a-cath placement, or any other central venous access placement.;4. No other chemotherapy, immunotherapy, hormonal anti-cancer therapy, radiotherapy (except for palliative local radiotherapy), biological therapy or other novel agent is permitted while the patient is receiving study medication. ;5. Grade >1 toxicity from prior therapy (except alopecia or anorexia).;6. Known malignant CNS disease other than neurologically stable, treated brain metastases * defined as metastasis having no evidence of progression or haemorrhage after treatment for at least 2 weeks (including brain radiotherapy). Must be off any systemic corticosteroids for the treatment of brain metastases for at least 14 days prior to enrolment.;7. Any prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4, which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug.
8. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) * Class 2:
a) Unstable angina
b) Congestive heart failure
c) Acute myocardial infarction
d) Conduction abnormality not controlled with pacemaker or medication
e) Significant ventricular or supraventricular arrhythmias (patients with chronic rate controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).;9. AZD1775 should not be given to patients with a history of Torsades de pointes unless all risk factors that contributed to Torsades have been corrected. AZD1775 has not ben studied in patients with ventricular arrhythmias or recent myocardial infarction.;10. Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome. QTc interval will be calculated using Fridericia's formula (per institutional standards) obtained from 3 ECGs performed 2-5 minutes apart at study entry.
11.Pregnant or lactating.;12. Serious active infection upon enrolment, or other serious underlying medical condition that would impair the patient's ability to receive study treatment. ;13. Presence of other active cancers, or history of treatment for invasive cancer within the last 3 years. Patients with Stage I cancer who have received definitive local treatment within the last 3 years, and whom are considered unlikely to recur, are eligible. All patients with previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are patients with prior non-melanoma skin cancers.;14. Psychological, familial, sociological, or geographic conditions that do not permit compliance with the protocol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-000886-30-NL |
| ClinicalTrials.gov | NCT02272790 |
| CCMO | NL62988.031.17 |