Protocol v1.0 31-Mar-2014, paragraph 2.1-2.4, pages 37-39:The primary objective of this study is: - To determine the efficacy of Olaparib maintenance monotherapy compared to placebo by progression free survival (PFS).The secundary objectives of this…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Protocol v1.0 31-Mar-2014, paragraph 2.1, page 37:
The primary outcome measure of this study is:
- Progression Free Survival (PFS) by BICR using modified RECIST 1.1.
Secondary outcome
Protocol v1.0 31-Mar-2014, paragraph 2.1-2.4, pages 37-39:
The secundary outcome measures of this study are:
- Overall Survival (observed and predicted using observed PFS and OS data).
- Time from randomisation to second progression (PFS2).
- Time from randomisation to first subsequent therapy or death (TFST).
- Time from randomisation to second subsequent therapy or death (TSST).
- Time from randomisation to study treatment discontinuation or death (TDT).
- Objective Response Rate by BICR using modified RECIST 1.1 criteria for
evaluable patients.
- Disease Control Rate at 16 weeks by BICR using modified RECIST 1.1 criteria.
- Adjusted mean change from baseline in global QoL score from the EORTC-QLQ-C30
questionnaire.
The safety outcome measure of this study is:
- Adverse event (AE), physical examination, vital signs including blood
pressure (BP), pulse, electrocardiogram (ECG) and laboratory findings including
clinical chemistry and haematology.
The exploratory outcome measures of this study are:
- Adjusted mean change from baseline on EORTC-QLQ-C30 functioning domains
(physical, role, cognitive, emotional, social), on EORTC-QLQ-C30 + PAN26
symptom scales and items (pain, fatigue, nausea, weight loss (difficulty
gaining weight/loss of appetite), jaundice and on performance status measured
by the ECOG Performance Status scale.
- Number, type and reason of hospitalisations and hospital attendances,
procedures undertaken and hospital length of stay.
- Health state utility derived from the HRQL instrument, the EuroQoL EQ5D.
- Overall survival adjusted for impact of subsequent PARP inhibitors (or other
potentially active investigational agents (if appropriate, to support
reimbursement appraisals).
- BRCA1 and/or BRCA2 mutation status in tumour.
- Potential tissue biomarkers identified.
Background summary
Protocol v1.0 31-Mar-2014, paragraph 1.1, pages 24 and 28:
[...] Despite the development of more *active* regimens for first treatment of
metastatic pancreatic cancer in the last decade, their limited absolute
benefit and significant toxicity strongly suggest that improving the results of
initial therapy of metastatic pancreas cancer constitutes an unmet medical
need. Furthermore to date there has been no marker, clinical or molecular that
would predict for increased likelihood of benefit from systemic therapies for
pancreas cancer.
[...]
Phase I and proof-of-concept phase II studies have shown that PARP inhibitors
have significant activity with limited toxicity when used as single
agents in the treatment of gBRCA1/2 mutation-associated breast and ovarian
cancer and pancreas cancer. The present trial is an important step in defining
the role of Olaparib as a PARP inhibitor in patients with deleterious germline
BRCA1/2 mutations and metastatic pancreas cancer and the strategy of switch
maintenance to prolong disease control after beneficial effect of a platinum
regimen as has been suggested for gBRCA-mutated ovarian cancer.
[...]
If the trial is successful it will give patients a relatively non-toxic oral
therapeutic which will delay progression after stopping first line platinum
based chemotherapy.
Study objective
Protocol v1.0 31-Mar-2014, paragraph 2.1-2.4, pages 37-39:
The primary objective of this study is:
- To determine the efficacy of Olaparib maintenance monotherapy compared to
placebo by progression free survival (PFS).
The secundary objectives of this study are:
- To determine the efficacy of Olaparib maintenance monotherapy compared to
placebo.
- To assess the effect of Olaparib on the Health-related Quality of Life
(HRQoL) as measured by EORTC QLQ-C30 global QoL scale.
The safety objective of this study is:
- To assess the safety and tolerability of Olaparib maintenance monotherapy.
The exploratory objectives of this study are:
- To assess the effect of Olaparib on functioning as measured by the EORTC
QLQ-C30 functioning domains (physical, role, cognitive, emotional and social).
- To assess the effect of Olaparib on pancreas cancer symptoms as measured by
the EORTC QLQ-PAN26 items and scales.
- To assess clinically relevant symptoms as measured by the EORTC QLQ-C30 and
PAN26, including pain, fatigue, nausea, weight loss (or difficulty gaining
weight/loss of appetite), jaundice.
- To assess change in performance status as measured by the ECOG Performance
Status scale.
- To investigate the health economic impact of treatment and the disease on
hospital related resource use and health state utility.
- To explore methods of estimating overall survival (OS) adjusting for the
impact of the control arm receiving subsequent Polyadenosine 5*diphosphoribose
[poly (ADP ribose)] polymerise (PARP) inhibitors or imbalances between the
treatment arms for other potentially active agents.
- To determine the frequency of and describe the nature of BRCA mutation/s in
tumour samples and to compare this with germline BRCA mutation status.
- To identify tumour tissue based biomarkers (including but not limited to
somatic BRCA1/2 mutations, BRCA methylation and/or other HRD biomarkers) that
could be used to guide future patient segmentation approaches for development
- Future exploratory research into factors that may influence development of
cancer and/or response to treatment (where response is defined broadly to
include efficacy, tolerability or safety) may be performed on the collected and
stored archival tumour samples (if available), blood samples at day 1 and on
disease progression or on residual tissue material collected as part of the
study.
Study design
Protocol v1.0 31-Mar-2014, paragraph 1.5, page 34:
This is a phase III, randomised, double-blind, placebo-controlled, multi-centre
study to assess the efficacy of Olaparib maintenance monotherapy in metastatic
pancreatic cancer patients with gBRCA mutations [documented mutation in gBRCA1
or gBRCA2] that is predicted to be deleterious or suspected deleterious (known
or predicted to be detrimental/lead to loss of function) and whose tumours have
not progressed on at least 16 weeks of first line platinum based chemotherapy.
Intervention
Protocol v1.0 31-Mar-2014, page 8-9:
Patients will be randomised (using an IVRS) in a 3:2 ratio (Olaparib:placebo)
to the treatments as specified below:
* Olaparib tablets po. 300 mg twice daily
* Placebo tablets twice daily
Investigational product, dosage and mode of administration Olaparib is
available as a green film-coated tablet containing 150 mg or 100 mg of
Olaparib. Patients will be administered study treatment orally at a dose of 300
mg twice daily (bid). The planned dose of 300 mg bid will be made up of two x
150 mg tablets bid with 100 mg tablets used to manage dose reductions.
Placebo will be available as green film-coated tablets matching the Olaparib
tablets. These should be taken as per instructions for Olaparib tablets.
Study burden and risks
Protocol v1.0 31-Mar-2014, paragraph 1.4
As of 2 October 2013, an estimated 2103 patients with ovarian, breast, gastric,
pancreas, and a variety of other solid tumours are estimated to have received
treatment with Olaparib across the dose range 10 mg qd to 600 mg bid in
AstraZeneca-sponsored, investigator-sponsored, and collaborative group studies.
Olaparib has been given as either monotherapy (18 studies, an estimated 1214
patients) or in combination with other chemotherapy/anticancer agents (25
studies, an estimated 889 patients). Many of these combinations studies are
ongoing.
The majority of patients to date have received the capsule formulation of
Olaparib (an estimated 1635 patients). Approximately 468 patients have received
the tablet formulation to date. Approximately 304 patients have received
comparator or placebo across the Olaparib development programme. An analysis of
monotherapy data across 12 AstraZeneca sponsored monotherapy studies in 975
patients who have been given Olaparib capsule estimated that 16.1% (157/975) of
patients had been exposed to Olaparib capsule for *12 months at the time of
database closure for the 12 studies. Furthermore, 41/ 975 patients received
treatment for >24 months (longest duration was 44 months).
From the available data to date, there is no evidence of any unexpected
toxicity following long-term Olaparib (capsule) monotherapy exposure. Olaparib
as monotherapy at doses up to 400 mg bid capsule is generally well tolerated,
with the most common AEs nausea, fatigue, vomiting, diarrhoea, upper abdominal
pain, dyspnoea, decreased appetite, dyspepsia, dizziness, headache, dysgeusia,
cough, leukopenia, neutropenia, thrombocytopenia and anaemia mainly
mild-to-moderate (CTCAE Grade * 2) in severity. In addition, in a small number
of patients MDS/AML or pneumonitis have been observed and identified as
important risks.
Pepparedsleden 1
Sodertalje SE-15185
SE
Pepparedsleden 1
Sodertalje SE-15185
SE
Listed location countries
Age
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:, 1.
*Provision of informed consent prior to any study specific procedures, 2.
*Patients must be male or female *18 years of age, 3. *Histologically or
cytologically confirmed pancreas adenocarcinoma receiving initial chemotherapy
for metastatic disease and without evidence of disease progression on
treatment, 4. Patients with measurable disease and/or non-measurable or no
evidence of disease assessed at baseline by CT (or MRI where CT is
contraindicated) will be entered in this study. , 5. Documented mutation in
gBRCA1 or gBRCA2 that is predicted to be deleterious or suspected deleterious
(known or predicted to be detrimental/lead to loss of function) , 6. Patients
are on treatment with a first line platinum-based regimen for metastatic
pancreas cancer, have received a minimum of 16 weeks of continuous platinum
treatment and have no evidence of progression based on investigator*s opinion.
, 7. Patients who have received platinum as potentially curative treatment for
a prior cancer (eg ovarian cancer) or as adjuvant/neoadjuvant treatment for
pancreas cancer are eligible provided at least 12 months have elapsed between
the last dose of platinum-based treatment and initiation of the platinum-based
chemotherapy for metastatic pancreas cancer., 8. Patients must have normal
organ and bone marrow function measured within 4 weeks prior to administration
of study treatment as defined below:, * Haemoglobin * 9.0 g/dL with no blood
transfusions (packed red blood cells and platelet transfusions) in the past 28
days, * Absolute neutrophil count (ANC) * 1.5 x 109/L, * White blood cells
(WBC) >3 x 109/L, * No features suggestive of MDS/AML on peripheral blood
smear, * Platelet count * 100 x 109/L, * Total bilirubin * 1.5 x institutional
upper limit of normal, * AST (SGOT)/ALT (SGPT) * 2.5 x institutional upper
limit of normal value unless liver metastases are present in which case they
must be * 5x ULN, * Serum creatinine * 1.5 x institutional upper limit of
normal (ULN), 9. *ECOG performance status 0-1 at date signing of informed
consent, 10. *Postmenopausal or evidence of non-childbearing status for women
of childbearing, potential: negative urine or serum pregnancy test.
Postmenopausal is defined as:, * Amenorrheic for 1 year or more following
cessation of exogenous hormonal, treatments, * Luteinizing hormone (LH) and
Follicle stimulating hormone (FSH) levels in, the post menopausal range for
women under 50, * Radiation-induced oophorectomy with last menses >1 year
ago, * Chemotherapy-induced menopause with >1 year interval since last
menses, * Surgical sterilisation (bilateral oophorectomy or hysterectomy), 11.
*Patient is willing and able to comply with the protocol for the duration of
the study including undergoing treatment and scheduled visits and examinations,
12. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary
tumour or a metastatic site if available or 3 unstained cytology slides if
available.
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria
are fulfilled:, 1. *Involvement in the planning and/or conduct of the study
(applies to AstraZeneca staff and/or staff at the study site)., 2. gBRCA1
and/or gBRCA2 mutations that are considered to be non detrimental (eg,
*Variants of uncertain clinical significance* or *Variant of unknown
significance* or *Variant, favour polymorphism* or *benign polymorphism*
etc.)., 3. Progression of tumour between start of first line platinum based
chemotherapy for metastatic pancreas cancer and randomisation., 4. Cytotoxic
chemotherapy or non-hormonal targeted therapy within 28 days of Cycle 1 Day 1
is not permitted. Palliative radiotherapy must have been completed 14 or more
days before Cycle 1 Day 1. 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 2 weeks prior to study treatment., 5.
*Previous randomisation in the present study., 6. Exposure to an
investigational product within 30 days or 5 half lives (whichever is, longer)
prior to randomisation, 7. *Any previous treatment with a PARP inhibitor,
including Olaparib., 8. *Patients with second primary cancer, EXCEPTIONS:
adequately treated nonmelanoma skin cancer, curatively treated in-situ cancer
of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial
carcinoma, or other solid tumours including lymphomas (without bone marrow
involvement) curatively treated with no evidence of disease for * 5 years prior
to study entry., 9. Resting ECG with QTc * 450 msec detected on 2 or more time
points within a 24 hour period or family history of long QT syndrome. If ECG
demonstrates QTc * 450 msec, patient will be eligible only if repeat ECG
demonstrates QTc *450 msec., 10. Concomitant use of known potent CYP3A4/5
inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir,
saquinavir, telithromycin, clarithromycin and nelfinavir., 11. Persistent
toxicities (*CTCAE grade 2) caused by previous cancer therapy, excluding
alopecia and CTCAE grade 3 peripheral neuropathy., 12. *Patients with
myelodysplastic syndrome/acute myeloid leukaemia., 13. Major surgery within 2
weeks of starting study treatment: patients must have recovered from any
effects of any major surgery., 14. *Immunocompromised patients, eg, patients
who are known to be serologically positive for human immunodeficiency virus
(HIV)., 15. *Clinically significant uncontrolled medical conditions are not
permitted (eg active infection requiring IV antibiotics, symptomatic congestive
heart failure, unstable angina pectoris, recent (3 months) myocardial
infarction, extensive bilateral interstitial lung disease, psychiatric illness
that would limit ability to comply with study procedures, and any other medical
condition that, in the opinion of the investigator, places the patient at
unacceptable risk of toxicity. NB: Diabetes which, is controlled by medication
does not exclude participation in the study, 16. *Patients with a history of
treated CNS metastases are eligible, provided they meet all of the following
criteria: Disease outside the CNS is present. No evidence of interim
progression between the completion of CNS-directed therapy and the screening
radiographic study. No history of intracranial haemorrhage or spinal cord
haemorrhage. Minimum of 2 weeks between completion of radiotherapy and cycle 1
Day 1 and recovery from significant (Grade *3) acute toxicity with no ongoing,
17. *Patients unable to swallow orally administered medication and patients
with, gastrointestinal disorders likely to interfere with absorption of the
study medication., 18. *Pregnant or breast feeding women., 19. *Previous
allogeneic bone marrow transplant., 20. *Patients with a known hypersensitivity
to Olaparib or any of the excipients of the, product., 21. *Whole blood
transfusions in the last 120 days prior to enrolment to the study, which may
interfere with gBRCA testing (packed red blood cells and platelet
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 | EUCTR2014-001589-85-NL |
| ClinicalTrials.gov | NCT02184195 |
| CCMO | NL50342.028.14 |