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Olaparib +/- Cediranib or Chemotherapy in Patients With Platinum-resistant Ovarian Cancer (OCTOVA)

Primary Purpose

Ovarian Cancer

Status
Active
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Olaparib
Cediranib
Paclitaxel
Sponsored by
University of Oxford
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ovarian Cancer focused on measuring BRCA1/2 mutation, Platinum resistance

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Female patients, age ≥ 16 years with relapsed epithelial ovarian, primary peritoneal or fallopian tube cancer who have relapsed within 12 months of previous platinum-based therapy. Their most recent chemotherapy does not have to have been platinum-based.
  2. Patients can have received prior PARP inhibitor, but there must be a > 6 month interval since treatment.
  3. Patients can have received prior antiangiogenic therapy, but there must be a > 6 month interval since treatment; except for bevacizumab where a 6 week interval is required.
  4. Measurable disease by RECIST Version 1.1 performed in past 4 weeks. At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
  5. Sufficient archival tissue confirming histological diagnosis available.
  6. ECOG PS 0-2
  7. Able to swallow and retain oral medications.
  8. Life expectancy > 12 weeks in terms of disease related mortality
  9. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  10. Written (signed and dated) informed consent prior to any study specific procedures and be capable of co-operating with protocol.
  11. Patients must have

    • Haemoglobin ≥ 9.0 g/dL and no blood transfusions in the 28 days prior to randomisation

  12. Patients must have normal organ and bone marrow function measured within 14 days prior to administration of study treatment as defined below:

    • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
    • Platelet count > 100 x 109/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 upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min calculated using Cockroft-Gault, Jelliffe or Wright (see Appendix 4)
    • Urine dipstick for proteinuria <2+. If urine dipstick is ≥ 2+ on two occasions more than one week apart then a 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours or protein/creatinine ratio < 1.5.

Exclusion Criteria:

  1. Received previous single agent weekly paclitaxel for relapsed disease.
  2. Pregnant or breast-feeding women or women of childbearing potential unless effective methods of contraception are used during the trial and for 6 months after stopping treatment. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. Pregnancy test will be performed monthly in women of child bearing potential.

    Postmenopausal is defined as:

    • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
    • LH and 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, or surgical sterilisation (bilateral oophorectomy or hysterectomy).
  3. Treatment with any other investigational agent, systemic chemotherapy, or participation in another interventional clinical trial within 28 days prior to enrolment.
  4. Radiotherapy within 2 weeks from the last dose prior to study treatment
  5. Started a stable dose of bisphosphonates for bone metastases less than 4 weeks prior to treatment with study drug e.g. patient is eligible and can continue to take bisphosphonates if these were started at least 4 weeks prior to treatment with study drug.
  6. Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir.
  7. Concomitant use of potent inducers of CYP3A4 such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John Wort.
  8. Persistent toxicities (>=CTCAE grade 2) caused by previous cancer therapy with the exception of alopecia.
  9. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
  10. Blood transfusions within 1 month prior to study start
  11. Patients with myelodysplastic syndrome/acute myeloid leukaemia.
  12. Patients with symptomatic, untreated, uncontrolled brain or meningeal metastases or tumour.

    a. A scan to confirm the absence of brain metastases is not required. b. Patients with radiological evidence of stable brain metastases are eligible, providing that they are asymptomatic and: i. Do not require corticosteroids, or ii. Have previously been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids iii. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment.

  13. Major surgery within 14 days of starting study treatment
  14. Patients who have not recovered from any effects of any major surgery.
  15. 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, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan
  16. Any psychiatric disorder that prohibits obtaining informed consent.
  17. Left Ventricular Ejection Fraction (LVEF) < institutional lower limit of normal, when:

    i. Prior treatment with anthracyclines (excluding liposomal doxorubicin) ii. Prior treatment with trastuzumab iii. A NYHA classification of II controlled with treatment (see Appendix 2) iv. Prior central thoracic RT, including RT to the heart v. History of myocardial infarction within the prior 12 months

  18. Poorly controlled hypertension (persistently elevated > 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication)
  19. History of inflammatory bowel disease
  20. History of cerebrovascular accident (including transient ischaemic attacks) within last 12 months.
  21. Gastro intestinal impairment that could affect ability to take, or absorption of, oral medicines including sub- acute or complete bowel obstruction
  22. Evidence of severe or uncontrolled cardiac disease
  23. Evidence of active bleeding or bleeding diathesis. Defined as significant haemorrhage (>30mL bleeding/episode in previous 3 months) or haemoptysis (>5mL fresh blood in previous 4 weeks)
  24. Known treatment-limiting hypersensitivity to cediranib, olaparib, paclitaxel or any of its excipients
  25. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
  26. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions, requiring treatment/or whose prognosis will prevent readout from trial endpoints.
  27. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.

28 Immunocompromised patients e.g., patients who are taking immunosuppressive drugs.

Sites / Locations

  • Belfast City Hospital
  • Mount Vernon Cancer Centre
  • City Hospital Nottingham
  • Royal Surrey County Hospital
  • Royal United Hospital
  • Velindre
  • Beatson West of Scotland Cancer Centre
  • Clatterbridge Cancer Centre
  • St Bartholomew's
  • Hammersmith Hospital
  • Royal Marsden Chelsea & Sutton
  • University College London
  • The Christie
  • Churchill Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Experimental

Arm Label

A: Paclitaxel

B: Olaparib

C: Olaparib and Cediranib

Arm Description

Paclitaxel, IV weekly, 80mg/m2; until progression

Olaparib, oral, 300mg twice daily; until progression

Olaparib, oral, 300mg twice daily and Cediranib, tablet, 20mg once daily; until progression

Outcomes

Primary Outcome Measures

Progression free survival
Progression free survival (PFS), measured as time from date of randomisation to RECIST-defined progression or death from any cause (whichever is first)

Secondary Outcome Measures

Adverse events
Adverse events using CTCAE v4.03
Overall Survival
Overall Survival
Objective Response Rate
Objective Response Rate based on RECIST v1.1
Objective Response Rate
Objective Response Rate based GCIG CA125
Quality of Life Outcomes
Quality of Life Outcomes based on EORTC-QLQ C30
Quality of Life Outcomes
Quality of Life Outcomes based on EQ5D
Quality of Life Outcomes
Quality of Life Outcomes based on OV28.

Full Information

First Posted
March 21, 2017
Last Updated
April 11, 2023
Sponsor
University of Oxford
Collaborators
AstraZeneca
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1. Study Identification

Unique Protocol Identification Number
NCT03117933
Brief Title
Olaparib +/- Cediranib or Chemotherapy in Patients With Platinum-resistant Ovarian Cancer
Acronym
OCTOVA
Official Title
Randomised Phase II Trial of Olaparib, Chemotherapy or Olaparib and Cediranib in Patients With Platinum-resistant Ovarian Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 9, 2017 (Actual)
Primary Completion Date
March 12, 2021 (Actual)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Oxford
Collaborators
AstraZeneca

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The trial will compare the drugs olaparib and cediranib with standard chemotherapy in platinum resistant ovarian cancer. Patients will be randomised to one of three treatment groups: olaparib only, olaparib and cediranib and the control group paclitaxel. The aim is to compare efficacy of the 3 treatments and also how well each treatment is tolerated including the participants quality of life.
Detailed Description
Olaparib is a PARP inhibitor which targets BRCA1/2 mutated tumour cells and cediranib is an anti-angiogenic drug which reduces blood supply to the tumour, suppressing tumour viability. Phase I/II trials of both drugs have shown these are well tolerated alone or in combination in ovarian cancer. The trial aims to compare the efficacy of the combination and of olaparib alone with paclitaxel chemotherapy and whether the olaparib/cediranib combination is better tolerated thus improving quality of life. Secondly standard paclitaxel chemotherapy must be administered weekly at hospital whereas the olaparib/cediranib combination can be administered at home potentially also improving patient quality of life. Participants' tumours will be resistant to platinum based therapies. Participants will be randomised into one of the 3 treatment arms after stratification for prior PARP/anti-angiogenic treatments/BRCA status. Participants will be on trial up to 18 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ovarian Cancer
Keywords
BRCA1/2 mutation, Platinum resistance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomised open label trial with 3 arms, stratified for prior PARP use, prior anti-angiogenic use and BRCA status.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
139 (Actual)

8. Arms, Groups, and Interventions

Arm Title
A: Paclitaxel
Arm Type
Active Comparator
Arm Description
Paclitaxel, IV weekly, 80mg/m2; until progression
Arm Title
B: Olaparib
Arm Type
Experimental
Arm Description
Olaparib, oral, 300mg twice daily; until progression
Arm Title
C: Olaparib and Cediranib
Arm Type
Experimental
Arm Description
Olaparib, oral, 300mg twice daily and Cediranib, tablet, 20mg once daily; until progression
Intervention Type
Drug
Intervention Name(s)
Olaparib
Intervention Description
Tablet, 100mg and 150mg
Intervention Type
Drug
Intervention Name(s)
Cediranib
Intervention Description
Tablet 15mg and 20mg
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Intervention Description
Intravenous (IV)
Primary Outcome Measure Information:
Title
Progression free survival
Description
Progression free survival (PFS), measured as time from date of randomisation to RECIST-defined progression or death from any cause (whichever is first)
Time Frame
up to 18 months
Secondary Outcome Measure Information:
Title
Adverse events
Description
Adverse events using CTCAE v4.03
Time Frame
up to 18 months
Title
Overall Survival
Description
Overall Survival
Time Frame
12 & 18 months
Title
Objective Response Rate
Description
Objective Response Rate based on RECIST v1.1
Time Frame
up to 18 months
Title
Objective Response Rate
Description
Objective Response Rate based GCIG CA125
Time Frame
up to 18 months
Title
Quality of Life Outcomes
Description
Quality of Life Outcomes based on EORTC-QLQ C30
Time Frame
up to 18 months
Title
Quality of Life Outcomes
Description
Quality of Life Outcomes based on EQ5D
Time Frame
up to 18 months
Title
Quality of Life Outcomes
Description
Quality of Life Outcomes based on OV28.
Time Frame
up to 18 months

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Female patients, age ≥ 16 years with relapsed epithelial ovarian, primary peritoneal or fallopian tube cancer who have relapsed within 12 months of previous platinum-based therapy. Their most recent chemotherapy does not have to have been platinum-based. Patients can have received prior PARP inhibitor, but there must be a > 6 month interval since treatment. Patients can have received prior antiangiogenic therapy, but there must be a > 6 month interval since treatment; except for bevacizumab where a 6 week interval is required. Measurable disease by RECIST Version 1.1 performed in past 4 weeks. At least one lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements. Sufficient archival tissue confirming histological diagnosis available. ECOG PS 0-2 Able to swallow and retain oral medications. Life expectancy > 12 weeks in terms of disease related mortality Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. Written (signed and dated) informed consent prior to any study specific procedures and be capable of co-operating with protocol. Patients must have • Haemoglobin ≥ 9.0 g/dL and no blood transfusions in the 28 days prior to randomisation Patients must have normal organ and bone marrow function measured within 14 days prior to administration of study treatment as defined below: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count > 100 x 109/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 upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min calculated using Cockroft-Gault, Jelliffe or Wright (see Appendix 4) Urine dipstick for proteinuria <2+. If urine dipstick is ≥ 2+ on two occasions more than one week apart then a 24-hour urine must demonstrate ≤ 1 g of protein in 24 hours or protein/creatinine ratio < 1.5. Exclusion Criteria: Received previous single agent weekly paclitaxel for relapsed disease. Pregnant or breast-feeding women or women of childbearing potential unless effective methods of contraception are used during the trial and for 6 months after stopping treatment. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. Pregnancy test will be performed monthly in women of child bearing potential. Postmenopausal is defined as: Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments LH and 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, or surgical sterilisation (bilateral oophorectomy or hysterectomy). Treatment with any other investigational agent, systemic chemotherapy, or participation in another interventional clinical trial within 28 days prior to enrolment. Radiotherapy within 2 weeks from the last dose prior to study treatment Started a stable dose of bisphosphonates for bone metastases less than 4 weeks prior to treatment with study drug e.g. patient is eligible and can continue to take bisphosphonates if these were started at least 4 weeks prior to treatment with study drug. Concomitant use of known CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir. Concomitant use of potent inducers of CYP3A4 such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John Wort. Persistent toxicities (>=CTCAE grade 2) caused by previous cancer therapy with the exception of alopecia. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or family history of long QT syndrome. Blood transfusions within 1 month prior to study start Patients with myelodysplastic syndrome/acute myeloid leukaemia. Patients with symptomatic, untreated, uncontrolled brain or meningeal metastases or tumour. a. A scan to confirm the absence of brain metastases is not required. b. Patients with radiological evidence of stable brain metastases are eligible, providing that they are asymptomatic and: i. Do not require corticosteroids, or ii. Have previously been treated with corticosteroids, with clinical and radiological evidence of stabilisation at least 10 days after discontinuation of steroids iii. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 28 days prior to treatment. Major surgery within 14 days of starting study treatment Patients who have not recovered from any effects of any major surgery. 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, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan Any psychiatric disorder that prohibits obtaining informed consent. Left Ventricular Ejection Fraction (LVEF) < institutional lower limit of normal, when: i. Prior treatment with anthracyclines (excluding liposomal doxorubicin) ii. Prior treatment with trastuzumab iii. A NYHA classification of II controlled with treatment (see Appendix 2) iv. Prior central thoracic RT, including RT to the heart v. History of myocardial infarction within the prior 12 months Poorly controlled hypertension (persistently elevated > 150/100mmHg, either systolic or diastolic or both, despite anti-hypertensive medication) History of inflammatory bowel disease History of cerebrovascular accident (including transient ischaemic attacks) within last 12 months. Gastro intestinal impairment that could affect ability to take, or absorption of, oral medicines including sub- acute or complete bowel obstruction Evidence of severe or uncontrolled cardiac disease Evidence of active bleeding or bleeding diathesis. Defined as significant haemorrhage (>30mL bleeding/episode in previous 3 months) or haemoptysis (>5mL fresh blood in previous 4 weeks) Known treatment-limiting hypersensitivity to cediranib, olaparib, paclitaxel or any of its excipients Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions, requiring treatment/or whose prognosis will prevent readout from trial endpoints. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. 28 Immunocompromised patients e.g., patients who are taking immunosuppressive drugs.
Facility Information:
Facility Name
Belfast City Hospital
City
Belfast
State/Province
County Antrim
ZIP/Postal Code
BT9 7AM
Country
United Kingdom
Facility Name
Mount Vernon Cancer Centre
City
Northwood
State/Province
Middlesex
Country
United Kingdom
Facility Name
City Hospital Nottingham
City
Nottingham
State/Province
Nottinghamshire
ZIP/Postal Code
NG5 1PB
Country
United Kingdom
Facility Name
Royal Surrey County Hospital
City
Guildford
State/Province
Surrey
ZIP/Postal Code
GU2 7XX
Country
United Kingdom
Facility Name
Royal United Hospital
City
Bath
Country
United Kingdom
Facility Name
Velindre
City
Cardiff
Country
United Kingdom
Facility Name
Beatson West of Scotland Cancer Centre
City
Glasgow
Country
United Kingdom
Facility Name
Clatterbridge Cancer Centre
City
Liverpool
Country
United Kingdom
Facility Name
St Bartholomew's
City
London
ZIP/Postal Code
EC1A 7BE
Country
United Kingdom
Facility Name
Hammersmith Hospital
City
London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Facility Name
Royal Marsden Chelsea & Sutton
City
London
Country
United Kingdom
Facility Name
University College London
City
London
Country
United Kingdom
Facility Name
The Christie
City
Manchester
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
ZIP/Postal Code
OX3 7LE
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33452192
Citation
Mansouri A, McGregor N, Dunn R, Dobbie S, Holmes J, Collins L, Nicum S. Randomised phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer (OCTOVA): a study protocol. BMJ Open. 2021 Jan 15;11(1):e041463. doi: 10.1136/bmjopen-2020-041463.
Results Reference
derived

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Olaparib +/- Cediranib or Chemotherapy in Patients With Platinum-resistant Ovarian Cancer

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