PDL-1 Inhibition and Focal Sensitizing Radiotherapy in Recurrent Ovarian/Primary Peritoneal/Fallopian Tube Cancers.

Study Overview
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Brief Summary
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It is postulated that focal sensitizing radiotherapy may potentiate the effectiveness of durvalumab. The purpose of this study is to test the safety and tolerability of 2 different dose levels of focal sensitizing radiation therapy given with durvalumab.

Detailed Description
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Durvalumab is a PDL-1 inhibitor, part of class of agents (called checkpoint inhibitors) designed to increase the ability of the immune system to recognize and work to eliminate cancers. Checkpoint inhibitors have been studied in recurrent ovarian, primary peritoneal and Fallopian cancers, and on their own show a low level of activity. Radiation therapy is usually used in women with recurrent ovarian, primary peritoneal and Fallopian cancers to palliate symptoms related to progressive disease. However, radiation is know to modify the cancer immune environment and to release tumour antigens. These actions may potentiate the function of immune checkpoint inhibitors.

Official Title
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Phase I (Safety Assessment) of Durvalumab (MEDI4736) With Focal Sensitizing Radiotherapy in Platinum Resistant Ovarian, Primary Peritoneal or Fallopian Tube Epithelial Carcinoma

Conditions
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Ovarian Cancer, Primary Peritoneal Carcinoma, Fallopian Tube Cancer

Intervention / Treatment
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* Radiation: Focal radiotherapy
* Drug: Durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of written informed consent prior to any study specific procedures Female patients aged 19 years and older Platinum-resistant (progression within 6 months of platinum based regimen) or platinum-refractory ovarian/fallopian tube/peritoneal origin. High grade serous, endometrioid, clear cell, mucinous, malignant mixed Mullerian tumor, and low grade serous histotypes are permitted. Non-epithelial tumours will not be permitted. ECOG performance status 0-1. No more than 2 lines of therapy in the platinum-resistant setting. No bowel obstructions within the preceding 6 months. Last radiation therapy treatment ≥3 months prior to enrollment. Expected survival >3 months. All patients much have at least one site of measurable disease as defined by RECIST criteria (v.1.1). All patients must have disease suitable for core biopsy and agree to study related biopsies. Disease suitable for biopsy can serve as radiation targets, but cannot be used for response assessment. All patients must have at least 2 additional sites of disease that serve are suitable radiation targets (see section 6.2.1). Lesions suitable for radiation targeting must meet all of the following criteria: each target must be > 4 cc in volume by standard imaging techniques, such as CT scan, MRI, or radiograph for each lesion, partial treatment of a tumour mass is permitted, but the treatment volume cannot be less than the equivalent of a 2cm sphere (4cc) and the two targets cannot be part of the same contiguous mass must be outside of previously irradiated fields 12. Adequate organ and marrow function Exclusion Criteria: Subjects who cannot meet all the radiation planning constraints will not be eligible for this trial. Participation in another clinical study with an investigational agent during the last 4 weeks. Concurrent enrolment in another clinical study, the only exception being observational (non-interventional) clinical studies. History of pneumonitis requiring treatment with steroids, or has a history of interstitial lung disease. Patients who have contraindications to receiving radiation therapy, such as: Rheumatoid Arthritis, connective tissue disorders, Lupus, scleroderma, CREST syndrome, Crohn's syndrome, Ulcerative colitis, or other conditions identified by the Radiation Oncologist as unsuitable for radiation therapy. Current or prior use of immunosuppressive medication within 28 days before the first dose of the study drug, with the exception of intra-nasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses, which must not exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Prior exposure to an anti-PD-1 or anti-PD-L1 antibody.(including durvalumab History of acute diverticulitis, intra-abdominal abscess, or GI obstruction. Previous severe hypersensitivity reaction to another monoclonal antibody (mAb). Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with Vitiligo, Grave's disease or psoriasis not requiring systemic treatment (within the past 2 years) or those with resolved childhood asthma/atopy are not excluded. Uncontrolled intercurrent illness including: infection requiring therapy, symptomatic congestive heart failure, uncontrolled hypertension (systolic blood pressure > 150 and diastolic blood pressure >100), unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses. Mean QT interval corrected for heart rate (QTc) ≥ 470 ms calculated from using Frediricia'sCorrection. Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid [HCV RNA] (qualitative) is detected). Previous clinical diagnosis of active tuberculosis. Receipt of a live attenuated vaccination within 30 days of study entry or within 30 days or receiving the study drug. History of another malignancy, with the exception of: Malignancy treated with curative intent without evidence of recurrence for ≥ 5 years Adequately treated non -melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease e.g. cervical carcinoma in situ Female patients who are pregnant, breast-feeding or of childbearing potential who are not employing an effective method of birth control (see Table 3). Any condition that, in the opinion of the investigator, would interfere with evaluation of the study drug or interpretation of patient safety or study.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Durvalumab and focal radiotherapy<br>Durvalumab 1500 mg IV every 28 days, and 2 fractions of focal sensitizing radiation with cycles 1 and 2 of treatment. | Radiation: Focal radiotherapy<br>* Focal sensitizing radiotherapy will be given at a starting dose level of 24 Gray (6 Gy X 4 fractions), and may be escalated to 32 Gy (8Gy X4 fractions).<br>Drug: Durvalumab<br>* Durvalumab 1500 mg IV every 28 days<br>* Other names: MEDI 4736;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the maximum tolerated dose of durvalumab combined with focal irradiation for use in recurrent ovarian cancer | The maximum tolerated dose will be defined by dose-limiting toxicities and serious adverse events. | First 4 weeks of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Objective Response rate as evaluated by RECIST (v 1.1) criteria 2) Progression free survival 3) Overall survival | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| CA-125 response rate | Using GCIG CA-125 response criteria | From date of study enrollment until confirmed CA-125 progression, through study completion, an average of 1 year | 
| Immune-related response rate | Using Immune-related response criteria | From date of study enrollment until confirmed immune-related disease progression, through study completion, an average of one1year |