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JOURNAL ONKOLOGIE – STUDIE
WoO

WoO: Window of Opportunity Trial of Olaparib and Durvalumab in Histologically Proven EOC

Rekrutierend

NCT-Nummer:
NCT04644289

Studienbeginn:
Mai 2022

Letztes Update:
09.08.2024

Wirkstoff:
Olaparib, Durvalumab

Indikation (Clinical Trials):
Ovarian Neoplasms, Carcinoma, Ovarian Epithelial

Geschlecht:
Frauen

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
AGO Research GmbH

Collaborator:
-

Studienleiter

Frederik Marmé, MD
Principal Investigator
Universitätsklinikum Mannheim, Frauenklinik

Kontakt

Studienlocations
(3 von 6)

Klinikum rechts der Isar, Technische Universität München, Klinik und Poliklinik für Frauenheilkunde
81675 München
(Bayern)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Holger Bronger, PD Dr. med.» Ansprechpartner anzeigen
Universitätsklinikum Carl Gustav Carus Dresden an der technischen Universität Dresden, Gynäkologisches Krebszentrum und Regionales Brustzentrum Dresden am Universitäts-KrebsCentrum
01307 Dresden
(Sachsen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Pauline Wimberger, Prof.» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

In total, 60 patients are planned to be enrolled in 2 consecutive cohorts (30 patients

per cohort) into the trial.

After histologic confirmation of high-grade epithelial non-mucinous, non-clear cell

ovarian cancer, patients will be treated in two consecutive cohorts (A, B) of 30 patients

each, with

A) olaparib alone or B) olaparib in combination with durvalumab

Treatment allocation will take place in two consecutive cohorts rather than by

randomization. This will allow to evaluate the safety and feasibility in a stepwise

approach. A trial steering committee (TSC) meeting will take place between the cohorts to

review safety and feasibility prior to starting the second cohort. The safety follow-up

of the first cohort will take 90 days as of the first dose of therapy.

The window-of-opportunity treatment phase will be followed by primary debulking surgery

and standard of care platinum based first-line chemotherapy at the discretion of the

investigator.

After completion of first-line chemotherapy patients who have not progressed during

first-line chemotherapy will receive the indicated standard maintenance treatment

according to the national S3-guideline and treating physician's choice. For patients who

have received all possible licensed treatment regimens according to the national

guideline or for whom further licensed treatment options are contraindicated, Olaparib

may be offered as investigational maintenance therapy for up to 24 months.

Ein-/Ausschlusskriterien

Inclusion Criteria:

WoO pre-treatment (screening phase):

1. Patients with presumed and previously untreated advanced stage ovarian cancer

planned to undergo laparoscopy for histologic diagnosis and treatment planning

2. Patients willing and able to comply with the study protocol for the duration of the

study including undergoing treatment and scheduled visits and examinations including

follow up

3. Patients able and willing to provide fresh frozen biopsy samples from laparoscopy as

well as primary debulking for translational endpoints as well as serial liquid

biopsies

4. Patients able and willing to provide formaldehyde-fixed paraffin embedded (FFPE)

tissue samples from laparoscopy and primary debulking surgery

5. Patients aged ≥18 years

6. Patients must be 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

7. Provision of signed and dated, written ICF for the mandatory biomarker and genetic

re-search as well as the clinical/therapeutic part of the study prior to any

mandatory study specific procedures, sampling, and analyses

8. Eastern cooperative oncology group (ECOG) performance status 0-1 (see Appendix 1)

9. Patients must have a life expectancy ≥16 weeks

10. Ability to take oral medication

11. Postmenopausal or evidence of non-childbearing status for women of childbearing

potential (WOCBP): negative serum pregnancy test within 28 days of study treatment

and confirmed neagtive urine or serum pregnancy test prior to treatment on day 1.

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)

12. Women of childbearing potential (WOCBP) and their partners, who are sexually active,

must agree to the use of 2 highly effective forms of contraception in combination.

This should be started from the signing of the informed consent and continue

throughout the period of taking study treatment and for at least 6 months after last

dose of study drug(s), or they must totally/truly abstain from any form of sexual

intercourse.

WoO treatment phase:

13. Confirmed advanced (FIGO IIB/III/IV) high-grade, non-mucinous, non-clear cell

epithelial ovarian, fallopian tube or primary peritoneal cancer or known (BReast

CAncer) BRCA mutation and any histologic type

14. Planned primary debulking surgery after confirmation of diagnosis and disease

evaluation during laparoscopy

15. Body weight >30kg

16. Patients must have normal organ and bone marrow function measured within 28 days

prior to administration of study treatment as defined below:

- Haemoglobin ≥10.0 g/dL with no blood transfusion in the past 28 days

- Absolute neutrophil count (ANC) ≥1.5×10^9/L

- Platelet count ≥100×10^9/L

- Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase

(SGOT) / alanine aminotransferase (ALT), serum glutamic pyruvate transaminase

(SGPT) ≤2.5 × institutional upper limit of normal unless liver metastases are

present in which case they must be ≤5×ULN. (cave: patients with intrahepatic

metastases affecting liver function test might not be candidates for primary

debulking surgery)

- Patients must have creatinine clearance estimated of ≥51 mL/min using the

Cockcroft-Gault equation or based on a 24 hour urine test:

Estimated creatinine clearance=((140-age [years])*weight (kg))/(serum creatinine

(mg/dL)*72)(* 0,85) 17. Patients must have successfully contributed blood and tissue

samples as per requirements.

Exclusion Criteria:

Medical conditions:

1. Disease requiring urgent surgical intervention

2. Evidence of significant uncontrolled concomitant disease that could affect

compliance with the study protocol

3. Significant uncontrolled symptom burden (e.g. but not necessarily limited to large

volume ascites, shortness of breath on exertion, pain requiring opioid medication,

signs of (sub)ileus

4. Uncontrolled intercurrent illness, including but not limited to, ongoing or active

infection, symptomatic congestive heart failure, recent (within 3 months) myocardial

infarction, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia,

interstitial lung disease, uncontrolled major seizure disorder, unstable spinal cord

compression, superior vena cava syndrome, 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.

5. Other malignancy unless curatively treated with no evidence of disease for ≥5 years

except: adequately treated non-melanoma skin cancer, curatively treated in situ

cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial

carcinoma. Patients with a history of localized triple negative breast cancer may be

eligible, provided they completed their adjuvant chemotherapy more than three years

prior to registration, and that the patient remains free of recurrent or metastatic

disease (optional criteria that is dependent on the patient population under

investigation).

6. Resting electrocardiography (ECG) indicating uncontrolled, potentially reversible

cardiac conditions, as judged by the investigator (eg., unstable ischemia,

uncontrolled symptomatic arrhythmia, conges-tive heart failure, QTcF prolongation

>500 ms, electrolyte disturbances, etc.), or patients with congenital long QT

syndrome.

7. 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

a. Patients with irreversible toxicity not reasonably expected to be exacerbated by

treatment with olaparib, durvalumab or the combination may be included only after

consultation with the coordinating investigator.

8. Patients with myelodysplastic syndrome/acute myeloid leukemia or with features

suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).

9. Brain metastases or spinal cord compression. Patients with suspected brain

metastases at screening should have an MRI (preferred) or CT each preferably with IV

contrast of the brain prior to study entry

10. 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.

11. Evidence of central nervous system (CNS) or leptomeningeal metastases.

12. 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.

13. Patients unable to swallow orally administered medication and patients with

gastrointestinal disorders or any status that might interfere with resorption of the

respective study drugs, e.g. parenteral nutrition, short bowel syndrome likely to

interfere with absorption of the study medication.

14. Immunocompromised patients, e.g., patients who are known to be serologically

positive for human immunodeficiency virus (HIV).

15. History of active primary immunodeficiency

16. Active infection including tuberculosis (clinical evaluation that includes clinical

history, physical examination and radiographic findings, and TB testing in line with

local practice), hepatitis B or hepatitis C.

1. Active HBV is defined by a known positive 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.

2. Patients positive for HCV antibody are eligible only if polymerase chain

reaction is negative for HCV RNA

17. ECOG performance status (PS) ≥2 or general condition that might interfere with the

compliance with the study protocol

18. Known allergy or hypersensitivity to any of the study drugs or any of the study drug

excipients.

Prior / concomitant therapy:

19. Prior antineoplastic therapy for ovarian, fallopian tube or primary peritoneal

cancer

20. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative

reasons) within 3 weeks prior to study treatment

21. Any concurrent chemotherapy, investigational medicinal product (IMP), biologic, or

hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for

non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable

22. Patients planned for neoadjuvant chemotherapy or deemed unresectable at laparoscopy

23. Concomitant use of known strong cytochrome P450 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 olaparib is 2

weeks.

24. 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 olaparib is 5 weeks for enzalutamide or phenobarbital and 3

weeks for other agents

25. Major surgery within 2 weeks of starting study treatment and patients must have

recovered from any effects of any major surgery

26. History of allogenic organ transplantation

27. Previous allogenic bone marrow transplant or double umbilical cord blood

transplantation (dUCBT).

28. Patients with a known hypersensitivity to olaparib or any of the excipients of the

product.

29. Prior treatment with olaparib or any other poly [ADP-ribose] polymerase (PARP)

inhibitor

30. Whole blood transfusions in the last 120 days prior to entry to the study (packed

red blood cells and platelet transfusions are acceptable, for timing refer to

inclusion criteria no. 16)

Other exclusions:

31. Patients who are pregnant or breast-feeding or patients of reproductive potential

who are not willing to employ effective birth control from screening to 6 months

after the last dose of study drug(s).

32. Involvement in the planning and/or conduct of the study

33. Participation in another interventional clinical study with an investigational

product during the last with the last 3 months.

34. 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.

35. Previous enrolment in the present study.

36. Judgement 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.

Additional Durvalumab-specific exclusion criteria for cohort B:

37. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy,

endocrine therapy, targeted therapy, biologic therapy, tumor embolization,

monoclonal antibodies) ≤28 days prior to the first dose of study drug. If sufficient

wash-out time has not occurred due to the schedule or pharmacokinetic (PK)

properties of an agent, a longer wash-out period will be required.

38. 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 coordinating investigator.

2. Patients with irreversible toxicity not reasonably expected to be exacerbated

by treatment with durvalumab may be included only after consultation with the

coordinating investigator.

39. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.

Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone

replacement therapy) is acceptable.

40. Major surgical procedure (as defined by the investigator) within 28 days prior to

the first dose of IP. Note: local surgery of isolated lesions for palliative intent

is acceptable.

41. History of allogenic organ transplantation.

42. 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], systemic lupus erythematosus, sarcoidosis

syndrome, or wegener syndrome [granulomatosis with polyangiitis, graves' disease,

rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to

this criterion:

1. Patients with vitiligo or alopecia

2. Patients with hypothyroidism (e.g., following hashimoto syndrome) stable on

hormone replacement

3. Any chronic skin condition that does not require systemic therapy

4. Patients without active disease in the last 5 years may be included but only

after consultation with the study physician

5. Patients with celiac disease controlled by diet alone

43. 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 (Adverse Events) AEs or compromise the ability of the

patient to give written informed consent.

44. History of another primary malignancy except for

1. Malignancy treated with curative intent and with no known active disease ≥5

years before the first dose of IMP and of low potential risk for recurrence

2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence

of disease

3. Adequately treated carcinoma in situ without evidence of disease

45. History of leptomeningeal carcinomatosis

46. Brain metastases or spinal cord compression. Patients with suspected brain

metastases at screening should have an MRI (preferred) or CT each preferably with IV

contrast of the brain prior to study entry.

47. 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)

48. Active infection including tuberculosis (clinical evaluation that includes clinical

history, physical examination and radiographic findings, and tuberculosis testing in

line with local practice), hepatitis B (known positive hepatitis B virus (HBV)

surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV

infection (defined as the presence of hepatitis B core antibody

[anti-hepatitis-B-core (HBc)] and absence of HBsAg) are eligible. Patients positive

for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is

negative for HCV RNA.

49. Current or prior use of immunosuppressive medication within 14 days before the first

dose of durvalumab. 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)

50. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP.

Note: patients, if enrolled, should not receive live vaccine whilst receiving IMP

and up to 30 days after the last dose of IMP.

51. Prior randomisation or treatment in a previous durvalumab clinical study regardless

of treatment arm assignment or other immunotherapies

52. Patients who have received prior anti-programmed cell death-protein 1(PD-1), anti

PD-L1 or anti-cytotoxic T-lymphocyte-associated protein 4 (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 rechallenged, and not currently require maintenance doses of >10 mg

prednisone or equivalent per day.

53. Patients planned for neoadjuvant chemotherapy (e.g. but not exclusively due to

extend of disease spread or poor general condition etc.).

54. (sub)ileus or signs of malignant bowel obstruction.

Studien-Rationale

Primary outcome:

1. Feasibility of the WoO procedure for olaparib alone (cohort a) & olaparib in combination with durvalumab (cohort b) (Time Frame - Between registration into the trial until 60 days after surgery or 60 days after the originally planned surgery date in case of switch of therapeutic strategy.):
Defined as the successful completion of the WoO therapy: - Relative dose intensity (RDI) of ≥80% - No treatment-related surgical delays - Adherence to therapeutic strategy - Lack of clinical progression prior to primary debulking surgery - No treatment-related toxicities of any grade that in the judgment of the investigator or surgeon significantly interfered with the subject's optimal perioperative management



Secondary outcome:

1. Safety of the WoO procedure (Time Frame - Between registration into the trial until 60 days after surgery or 60 days after the originally planned surgery date in case of switch of therapeutic strategy.):
Evaluated by the proportion of patients who experience any adverse event (CTCAE v5.0), of a grade ≥3.

2. Proportion of circulating tumor DNA (ctDNA) Mutation positive patients (Time Frame - At baseline):
Proportion of ctDNA mutation positive patients at baseline above a predefined a cut-off (copies/ml).

3. CDR21 (Time Frame - At day 21):
Circulating DNA ratio at day 21 (CDR21) defined as the ratio of mutation abundance at day 21 relative to baseline of the mutant ctDNA allele with the highest abundance (mutant copies/ml) at baseline.

Studien-Arme

  • Other: cohort A - olaparib monotherapy
    Olaparib tablets 2 × 300 mg per day for 3 weeks prior to surgery until one day prior to surgery or withdrawal of informed consent and as long as the patient has received all possible licensed treatment regimens according to national guideline or for whom further licensed treatment options are contraindicated, offered as investigational maintenance therapy for 24 months after completion of primary therapy (chemotherapy).
  • Other: cohort B - olaparib + durvalumab combination
    Olaparib tablets 2 × 300mg per day for 4 weeks plus durvalumab 1500mg iv as a single dose prior to surgery (corresponding to 1 single cycle).

Geprüfte Regime

  • olaparib (Lynparza):
    Olaparib tablets are administrated orally 300 mg twice daily.
  • durvalumab (Imfinzi):
    Durvalumab is administered 1500mg iv as a single dose prior to surgery (corresponding to 1 single cycle) .

Quelle: ClinicalTrials.gov


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