Trial Title:
NEoadjuvant Olaparib Combination OvArian Cancer Targeted Study
NCT ID:
NCT06650709
Condition:
Ovarian Cancer Stage IV
Conditions: Official terms:
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Bevacizumab
Durvalumab
Olaparib
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Single arm, open label study.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Olaparib
Description:
Olaparib 300mg orally twice daily on a continuous dosing schedule for a maximum of 3 x
28-day cycles.
Arm group label:
Olaparib-Durvalumab-Bevacizumab
Intervention type:
Drug
Intervention name:
Bevacizumab
Description:
Bevacizumab 10mg/kg intravenously on Day 1 and 15 of the 28 day cycle for a maximum of 3
cycles (Cycle 3, Day 15 will be omitted).
Arm group label:
Olaparib-Durvalumab-Bevacizumab
Other name:
biosimilar
Intervention type:
Drug
Intervention name:
Durvalumab
Description:
Durvalumab 1500mg intravenously on Day 1 of the 28 day cycle for a maximum of 3 cycles.
Arm group label:
Olaparib-Durvalumab-Bevacizumab
Summary:
The goal of this phase 2 clinical trial is to learn if the three treatments olaparib,
durvalumab and bevacizumab can treat participants with a diagnosis of stage 4 high grade
serous ovarian cancer that is too advanced to undergo upfront surgery.
The main questions it aims to answer are:
Is the treatment able to shrink the cancer sufficiently for participants to undergo
surgery? Is the combination of treatments safe in this neoadjuvant (before surgery)
setting? This is a single arm study with no comparator arm.
Participants will receive the treatment up to 3 cycles with each drug given as follows in
a 28-day cycle:
Olaparib orally on a twice daily continuous dosing schedule Durvalumab given
intravenously on day 1 Bevacizumab given intravenously on day 1 and 15 (Day 15 omitted in
C3)
Participants will be assessed throughout the study for safety and efficacy endpoints
Detailed description:
This is a single arm, proof of concept phase 2 study. Subjects with a suspected or
confirmed diagnosis of high grade serous ovarian cancer who are not thought to be
candidates for primary debulking surgery and are considered candidates for neoadjuvant
chemotherapy and are not known to have BRCA mutation associated HGSOC will be considered
for the trial.
Patients will be given the following triplet therapy for 2 cycles: Olaparib 300mg PO BID
continuous dosing, Durvalumab 1500mg IV day 1, Bevacizumab 10mg/kg IV on day 1 and 15 of
a 28-day cycle.
Patients that respond to the therapy following 2 cycles will receive 1 further cycle
followed by interval cytoreductive surgery planned 3-4 weeks after completion of cycle 3
and at least 28 days from the last dose of Bevacizumab.
Following surgery, patients will revert back to standard of care (SOC) treatment and
receive up to 6 cycles of chemotherapy followed by SOC recommended maintenance treatments
as determined by the local treating oncology teams.
All subsequent treatments received and their response will be recorded as part of the
study data collection up to and including first documented progression.
Patients that do not respond to the therapy after 2 cycles will discontinue the triplet
therapy and switch to salvage standard of care treatment.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF) and in this
protocol. Written informed consent and any locally required authorization obtained
from the patient/legal representative prior to performing any protocol-related
procedures, including screening evaluations
2. Histologically proven high grade serous ovarian/ fallopian tube or primary
peritoneal cancer.
3. Chemotherapy naïve for high grade serous ovarian/ fallopian tube or primary
peritoneal cancer.
4. FIGO Stage IVA/B disease not suitable for primary debulking surgery but must have
the intention of proceeding to interval surgical debulking if treatment response is
demonstrated
5. Patients must have disease amenable to pre-operative screening biopsies for
additional translational endpoints or availability of sufficient archival tissue for
additional translational endpoints including HRR pathway testing.
6. At least one measurable lesion that can be accurately assessed at baseline by
computed tomography (CT) (or magnetic resonance imaging [MRI] where CT is
contraindicated) and is suitable for repeated assessment as per RECIST 1.1. The
baseline scan must be obtained within 28 days prior to the first dose of study
treatment.
7. Age ≥18 years.
8. Body weight >30 kg
9. ECOG performance status 0-1 within 7 days of study registration.
10. Life expectancy of > 4 months.
11. Normal organ and bone marrow function within 14 days prior to first dose, including:
1. Platelets ≥100x109/L
2. Hemoglobin ≥10 g/dL with no blood transfusion in the past 28 days
3. ANC ≥ 1.5 X 109/L
4. Total bilirubin ≤1.5 x upper limit of normal (ULN) unless due to Gilbert's
syndrome
5. AST (SGOT) & ALT (SGPT) ≤2.5×ULN, unless liver metastases are present, in which
case they must be ≤5×ULN
6. Estimated creatinine clearance ≥51 mL/min using the Cockroft-Gault equation or
based on a 24 hour urine test
12. Females of childbearing potential who are sexually active with a non-sterilized male
partner must agree to use at least 1 acceptable method of contraception from the
time of signing of the informed consent, throughout the period of taking study
treatment and for at least 6 months after last dose of olaparib, for at least 6
months after last dose of Bevacizumab, and at least 90 days from the last dose of
durvalumab, or they must totally/truly abstain from any form of sexual intercourse
during these time periods.
Non-sterilized male partners of a female patient must use male condom plus
spermicide throughout this period.
Cessation of birth control after this point should be discussed with a responsible
physician. Not engaging in sexual activity for the total duration of the drug
treatment and the drug washout period is an acceptable practice; however, periodic
abstinence, the rhythm method, and the withdrawal method are not acceptable methods
of birth control.
13. Postmenopausal or evidence of non-childbearing status for women of childbearing
potential: negative urine or serum pregnancy test within 28 days of study treatment
and confirmed prior to treatment on day 1. Postmenopausal is defined as:
1. Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments
2. Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50
3. radiation-induced oophorectomy with last menses >1 year ago
4. chemotherapy-induced menopause with >1 year interval since last menses
5. surgical sterilisation (bilateral oophorectomy or hysterectomy)
14. Ability to understand and the willingness to sign a written informed consent
document.
15. Subject's willingness and ability to comply with scheduled visits, treatment plans,
on study biopsies, laboratory tests, and other study procedures.
Exclusion Criteria:
1. Known germline BRCA1/2 mutation carriers or known somatic BRCA1/2 mutation
associated HGSOC (prior to screening)
2. History of allergic reactions attributed to compounds of similar chemical or
biologic composition to the Triplet Combination (olaparib, durvalumab, bevacizumab).
3. Use of any other anti-cancer therapy including systemic, targeted, immunotherapy,
hormonal, biological, chemotherapy, other novel agents or investigational agents
within 4 weeks of registration.
4. Participation in another clinical trial with an investigational product within 4
weeks of registration
5. Previous treatment with an immune checkpoint inhibitor, including durvalumab study
regardless of treatment arm assignment
6. Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
7. Previously received a PARP/VEGF/PD/L-1/CTLA4 targeted therapy for this cancer
diagnosis or any other cancer diagnosis in the last 5 years.
8. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4:
1. Must not have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy.
2. All AEs while receiving prior immunotherapy must have completely resolved or
resolved to baseline prior to screening for this study.
3. Must not have experienced a ≥Grade 3 immune related AE or an immune related
neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are
stably maintained on appropriate replacement therapy and are asymptomatic.
4. Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, not have experienced recurrence of
an AE if re-challenged, and not currently require maintenance doses of > 10 mg
prednisone or equivalent per day.
9. Other malignancy within the last 5 years except: adequately treated non-melanoma
skin cancer, curatively treated in situ cancer of the cervix, ductal breast
carcinoma in situ, Stage 1, grade 1 endometrial carcinoma, or other solid tumors
(without bone marrow involvement) curatively treated with no evidence of disease for
≥5 years.
10. Patients considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within
3 months) myocardial infarction, uncontrolled major seizure disorder, unstable
spinal cord compression, superior vena cava syndrome, extensive interstitial
bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any
psychiatric disorder that prohibits obtaining informed consent.
11. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication
12. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
judged by the investigator (e.g. unstable ischemia, uncontrolled symptomatic
arrhythmia, congestive heart failure, QTcF prolongation >470 ms, electrolyte
disturbances, etc.), or patients with congenital long QT syndrome.
13. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
14. Any unresolved toxicity (NCI CTCAE grade ≥2) from previous anticancer therapy, with
the exception of alopecia, vitiligo, and the laboratory values defined in the
inclusion criteria.
1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis
after consultation with the sponsor.
2. Patients with irreversible toxicity not reasonably expected to be exacerbated
by treatment with durvalumab may be included only after consultation with the
sponsor.
15. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML.
16. Major surgery within 2 weeks of starting study treatment and patients must have
recovered from any effects of any major surgery.
17. Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
18. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially
increase risk of incurring AEs or compromise the ability of the patient to give
written informed consent
19. History of leptomeningeal carcinomatosis
20. Patients with a contraindication to the use of Bevacizumab including perceived risk
of perforation and uncontrolled bleeding or clotting disorder, patients with current
signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel
obstruction within 28 days before study enrollment.
21. Concomitant use of known strong cytochrome P450 (CYP) 3A (CYP3A) inhibitors (eg,
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with
ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir)
or moderate CYP3A inhibitors (eg, ciprofloxacin, erythromycin, diltiazem,
fluconazole, verapamil). The required washout period prior to starting study
treatment is 2 weeks. Concomitant use of known strong (eg, phenobarbital,
enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine,
nevirapine and St John's Wort) or moderate CYP3A inducers (eg, bosentan, efavirenz,
modafinil). The required washout period prior to starting study treatment is 5 weeks
for enzalutamide or phenobarbital land 3 weeks for other agents. Please refer to
Table 3 for full details
22. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the
absence of brain metastases is not required. The patient can receive a stable dose
of corticosteroids before and during the study as long as these were started at
least 4 weeks prior to treatment. Patients with spinal cord compression unless
considered to have received definitive treatment for this and evidence of clinically
stable disease for 28 days.
23. History of active primary immunodeficiency. Human immunodeficiency virus (HIV)
positive (positive HIV 1/2 antibodies) patients must have undetectable virology.
Active tuberculosis infection (clinical evaluation that may include clinical
history, physical examination and radiographic findings, or tuberculosis testing in
line with local practice) is not allowed.
24. Patients with known active hepatitis (i.e., hepatitis B or C). Active hepatitis B
virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result.
Patients with a past or resolved HBV infection (defined as the presence of hepatitis
B core antibody and absence of HBsAg) are eligible. Patients positive for hepatitis
C virus (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
25. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy.
26. Receipt of live attenuated vaccine within 30 days prior to enrolment
27. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], celiac disease, irritable bowel disease, or other
serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus
erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.])
within the past 3 years prior to the start of treatment. The following are
exceptions to this criterion:
1. Patients with vitiligo or alopecia
2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) and stable on
hormone replacement therapy
3. Any chronic skin condition that does not require systemic treatment
4. Patients without active disease in the last 5 years may be included but only
after consultation with the study sponsor
5. Patients with celiac disease controlled by diet alone
28. Current or prior use of immunosuppressive medication within 14 days before the first
dose of enrolment. The following are exceptions to this criterion:
1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g.
intra-articular injection)
2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
3. Steroids as premedication for hypersensitivity reactions (e.g. CT scan
premedication).
29. Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration, or may interfere with the interpretation of study results, and
in the judgment of the investigator would make the subject inappropriate for entry
into this study.
30. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
November 1, 2024
Completion date:
November 1, 2028
Lead sponsor:
Agency:
British Columbia Cancer Agency
Agency class:
Other
Collaborator:
Agency:
AstraZeneca
Agency class:
Industry
Collaborator:
Agency:
Ozmosis Research Inc.
Agency class:
Industry
Source:
British Columbia Cancer Agency
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06650709
