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An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)

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ClinicalTrials.gov Identifier: NCT03699449
Recruitment Status : Recruiting
First Posted : October 8, 2018
Last Update Posted : December 14, 2018
Sponsor:
Collaborators:
AstraZeneca
Samsung Genomic Institute
Seoul National University Hospital
Samsung Medical Center
Korean Gynecologic Oncology Group
Information provided by (Responsible Party):
Yonsei University

Brief Summary:

This study is a pilot study of biomarker-driven targeted therapy in patients with platinum-resistant recurrent ovarian cancer. More specifically, this is a randomized, multi-center, open label, phase II study for Homologous Recombination Deficiency(HRD)+ patients and a biomarker-driven multiple-arm phase II study for Homologous Recombination Deficiency(HRD)- patients.

This study will consist of a number of study modules (substudies), each evaluating the antitumor activity of targeted agents in patients whose tumors express specific phenotype relevant to the molecules under investigation.


Condition or disease Intervention/treatment Phase
Platinum-resistant Recurrent Ovarian Cancer Drug: olaparib+cediranib combination therapy Drug: durvalumab + olaparib combination therapy Drug: durvalumab + chemotherapy treatment Drug: durvalumab + tremelimumab + chemotherapy treatment Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is a randomized, multi-center, open label, phase II study for HRD+ patients and a biomarker-driven multiple-arm phase II study for HRD- patients.

This study will consist of a number of study modules (substudies), each evaluating the antitumor activity of targeted agents in patients whose tumors express specific phenotype relevant to the molecules under investigation.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An uMbrella Study of BIomarker-driven Targeted Therapy In Patients With Platinum-resistant Recurrent OvariaN Cancer(AMBITION)
Actual Study Start Date : November 26, 2018
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2022


Arm Intervention/treatment
Experimental: olaparib + cediranib
olaparib+cediranib combination therapy
Drug: olaparib+cediranib combination therapy
Cediranib (30mg p.o. qd) + Olaparib (200mg p.o. bid) until disease progression

Experimental: durvalumab + olaparib
durvalumab + olaparib combination therapy
Drug: durvalumab + olaparib combination therapy
Durvalumab (1500mg i.v. every 4 weeks starting on week 5 day1 for up to 12 months) + Olaparib (300mg p.o. bid) until disease progression

Experimental: durvalumab + chemotherapy
durvalumab +chemotherapy
Drug: durvalumab + chemotherapy treatment

Durvalumab (1500mg i.v. every 4 weeks for up to 12 months) + non-platinum-based standard of care chemotherapy (weekly paclitaxel, topotecan, or Pegylated liposomal doxorubicin(PLD) up to 6 cycles)

Chemotherapy regimen:

Weekly Paclitaxel 80mg/m2 (day 1,8,15,22 every 4 weeks), PLD (40mg/m2 on D1 every 4 weeks), topotecan (4mg/m2 on D1,8,15 every 4 weeks)


Experimental: durvalumab + tremelimumab + chemotherapy
durvalumab + tremelimumab + chemotherapy
Drug: durvalumab + tremelimumab + chemotherapy treatment

Durvalumab (1500mg i.v. every 4 weeks for up to 12 months) + Tremelimumab (75mg i.v. every 4 weeks for up to 4 doses) + non-platinum-based standard of care chemotherapy (weekly paclitaxel, topotecan, or Pegylated liposomal doxorubicin (PLD) up to 4 cycles)

Chemotherapy regimen:

Weekly Paclitaxel 80mg/m2 (day 1,8,15,22 every 4 weeks), PLD (40mg/m2 on D1 every 4 weeks), topotecan (4mg/m2 on D1,8,15 every 4 weeks)





Primary Outcome Measures :
  1. objective response rate by RECIST 1.1 [ Time Frame: 6 months after treatment initiation ]
    The primary endpoint of the study is objective response rate by RECIST 1.1 (Time frame: up to 6 months after treatment initiation)


Secondary Outcome Measures :
  1. Progression-free survival(PFS) [ Time Frame: up to 3 years ]
  2. overall-survival(OS) [ Time Frame: up to 3 years ]
  3. immune-related Response Criteria [ Time Frame: up to 3 years ]
  4. Duration of response [ Time Frame: up to 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Female aged 20 years older
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancers.
  • Disease progression within 6 months of completing platinum-based chemotherapy
  • Who had received ≥ two lines of chemotherapy
  • Provision of informed consent prior to any study specific procedures
  • Female aged 20 years older at time of study entry
  • Body weight >30kg
  • Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: 1) Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days, 2) Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 3) Platelet count ≥ 100 x 109/L, 4) Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN), 5) Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 3 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN, 6) Patients must have creatinine clearance estimated using the Cockcroft-Gault equation of ≥50 mL/min: Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72, 7) a where F=0.85 for females and F=1 for males, 8) Urine protein: creatinine ratio (UPC) ≤1 OR ≤2+ proteinuria on two consecutive dipsticks taken no less than 1 week apart. Patients with 2+ proteinuria on dipstick must also have UPC <0.5 on 2 consecutive samples. 9) Adequately controlled blood pressure (systolic blood pressure (SBP) ≤140 mmHg; diastolic blood pressure (DBP) ≤ 90mmHg) on maximum of 3 antihypertensive medications. Patients must have a blood pressure (BP) of ≤ 140/90 mmHg taken in the clinic setting by a medical professional within 2 weeks prior to starting study. It is strongly recommended that patients who are on three antihypertensive medications be followed by a cardiologist or a primary care physician for management of BP while on study. 10) Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Patients must have a life expectancy ≥ 16 weeks.
  • 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)
  • Patients is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
  • Patients must have evaluable disease - define as one of the following: 12.1 RECIST 1.1 measurable disease OR, 12.2 Evaluable disease (defined as solid and cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions OR ascites and/or pleural effusion that has been pathologically demonstrated to be disease-related) in the setting of a CA125 > 2 times ULN.
  • Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must be available for central testing. If there is not written confirmation of the availability of an archived tumour sample prior to enrolment the patient is not eligible for the study. For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker research, patients must fulfil the following criteria: 1) Provision of informed consent for genetic research, 2) Provision of informed consent for biomarker research
  • If a patient declines to participate in the optional exploratory genetic research or the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.

Exclusion Criteria:

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Previous enrollment or randomization in the present study
  • Participation in another clinical study with an investigational product during the last 60 months
  • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  • Any previous treatment with poly ADP ribose polymerase(PARP) inhibitor (including olaparib), anti-PD-1, PD-L1, CTLA-4 (including durvalumab and tremelimumab).
  • Other malignancy within the last 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, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for ≥5 years. Patients with a history of localised 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
  • Resting ECG with Corrected QT Interval(QTc) > 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
  • Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
  • Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolization, monoclonal antibodies) ≤21 days prior to the first dose of study drug If sufficient wash-out time has not occurred due to the schedule or Pharmacokinetics(PK) properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigator
  • 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.
  • Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
  • Concomitant use of known strong 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.
  • 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.
  • 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 Principal Investigator. 2) Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Principal Investigator.
  • Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of Myelodysplastic syndrome/Acute myeloid leukemia(MDS/AML).
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03699449


Contacts
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Contact: Jung-Yun Lee, MD, Ph.D 82-2-2228-2246 JUNGYUNLEE@yuhs.ac

Locations
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Korea, Republic of
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 03080
Contact: Jae-Woen Kim, MD, Ph.D    +82-2-2072-3511    kjwksh@snu.ac.kr   
Principal Investigator: Jae-Woen Kim, MD, Ph.D         
Yonsei University Health System, Severance Hospital Recruiting
Seoul, Korea, Republic of, 03722
Contact: Jung-Yun Lee    82-2-2228-2230    jungyunlee@yuhs.ac   
Samsung Medical Center Recruiting
Seoul, Korea, Republic of, 06351
Contact: Byoung-Gie Kim, MD, Ph.D    82-2-3410-3513    bgkim@skku.edu   
Principal Investigator: Byoung-Gie Kim, MD, Ph.D         
Sponsors and Collaborators
Yonsei University
AstraZeneca
Samsung Genomic Institute
Seoul National University Hospital
Samsung Medical Center
Korean Gynecologic Oncology Group
Investigators
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Principal Investigator: Jung-Yun Lee, MD, Ph.D Severance Hospital

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Responsible Party: Yonsei University
ClinicalTrials.gov Identifier: NCT03699449     History of Changes
Other Study ID Numbers: 4-2018-0749
KCT0003283 ( Other Identifier: CRIS )
KGOG3045 ( Other Identifier: KGOG )
2018-10-009 ( Other Identifier: Samsung Medical Center )
1810-035-977 ( Other Identifier: Seoul National Univ. Hosp )
ESR-17-12678 ( Other Identifier: AstraZeneca )
First Posted: October 8, 2018    Key Record Dates
Last Update Posted: December 14, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Study protocol and even raw data will be released after further discussion among researchers.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Adnexal Diseases
Genital Diseases, Female
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Durvalumab
Olaparib
Tremelimumab
Cediranib
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors