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Randomized Phase II Trial of Durvalumab (MEDI4736) and Tremelimumab Administered in Combination Versus Sequentially in Recurrent Platinum-Resistant Epithelial Ovarian Cancer (NCT03026062)

AstraZeneca
The goal of this clinical research study is to test 2 types of dosing schedules of tremelimumab and durvalumab to learn if one is more effective in patients with high-grade, platinum-resistant epithelial ovarian, peritoneal, or fallopian tube cancer. The safety of the dosing schedules will also be studied.
  • Drug: Tremelimumab
    Arm 1, Sequential: 3 mg/kg intravenous (IV) every 4 weeks (q4w) for up to 4 doses Arm 2, Combination: 1 mg/kg IV plus Durvalumab for up to 4 doses
    • Ticilimumab
  • Drug: Durvalumab
    Arm 1, Sequential: 1.5 g IV q4w for up to 9 doses upon progression Arm 2, Combination: 1.5g IV q4w for up to 4 doses and then if disease progresses, by Durvalumab monotherapy 1.5 g IV q4w for up to 9 doses
    • MEDI4736
Ages eligible for Study
18 Years and older
Genders eligible for Study
All
Accepts Healthy Volunteers
No
Inclusion Criteria:
  • Written informed consent and any locally-required authorization (e.g., HIPAA in the USA, EU Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol-related procedures, including screening evaluations.
  • Age >/= 18 years at time of study entry.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Adequate normal organ and marrow function as defined by: Hemoglobin >/= 9.0 g/dL (transfusion is allowed to correct anemia); Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L (> 1500 per mm^3); Platelet count >/= 100 x 10^9/L (>100,000 per mm^3); Serum bilirubin </= 1.5 x institutional upper limit of normal (ULN) unless diagnosed with Gilbert's syndrome; AST and ALT </= 2.5 x ULN unless liver metastases are present, in which case it must be </= 5x ULN; Serum creatinine CL >40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance: Creatinine CL (mL/min) = [Weight (kg) x (140 - Age) x 0.85]/[72 x serum creatinine (mg/dL)].
  • Subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >/= 60 years old and no menses for >/= 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including biopsies and follow up.
  • Histology (reviewed at MDACC) showing recurrent high grade epithelial ovarian, peritoneal, or fallopian tube cancer.
  • Platinum resistant or refractory disease as defined by progression of disease on a platinum-containing regimen or recurrence of disease within 180 days of previous platinum treatment.
  • Have measurable disease based on modified RECIST 1.1. For the purposes of this study measurable disease is defined at least one "target" lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each target lesion must be >20 mm when measured by conventional techniques, including palpation, plain x-ray, CT, and MRI, or >10 mm when measured by spiral CT. The target lesion must be distinct from other tumor areas selected for pre-treatment biopsies. Pre-treatment imaging must be performed within 4 weeks of starting therapy.
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 administered during the last 28 days.
  • Any previous treatment with adoptive T cells therapy, a PD1 or PDL1 inhibitor, including Durvalumab or any anti-CTLA4 therapy, including Tremelimumab.
  • History of another primary malignancy except for: malignancy treated with curative intent and with no known active disease >/= 5 years before the first dose of study drug and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; or adequately treated carcinoma in situ without evidence of disease, e.g., cervical cancer in situ.
  • Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) </= 28 days prior to the first dose of study drug (</= 21 days prior to the first dose of study drug for subjects who have received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and </= 6 weeks for nitrosourea, mitomycin C, or bevacizumab). (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.)
  • Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's Correction.
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of Durvalumab OR Tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroid premedication for the prevention of radiologic contrast hypersensitivity is allowed.
  • Any unresolved toxicity (> CTCAE grade 1) from previous anti-cancer therapy, excluding alopecia. Subjects with irreversible toxicity greater than grade 1 that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy).
  • Any prior Grade >/= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > Grade 1.
  • Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
  • Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
  • History of primary immunodeficiency.
  • History of allogeneic organ transplant.
  • History of hypersensitivity to Durvalumab, Tremelimumab, or any excipient.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
  • Known history of previous clinical diagnosis of tuberculosis.
  • History of leptomeningeal carcinomatosis or brain metastasis.
  • Unresolved partial or complete small or large bowel obstruction.
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving Durvalumab OR Tremelimumab.
  • Subjects who are pregnant, breast-feeding or of reproductive potential who are not employing an effective method of birth control or are not willing to employ effective birth control from screening to 180 days after the last dose of Durvalumab + Tremelimumab combination therapy or 90 days after the last dose of Durvalumab monotherapy, whichever is the longer time period.
  • Any medical, social, or psychological condition that would interfere with evaluation of study treatment or interpretation of patient safety or study results.
  • Subjects with uncontrolled seizures.
  • Non-English speakers will be excluded from participating in the patient-reported outcomes component of the study.
Study Groups:

If participant is found to be eligible to take part in this study participant will be randomly assigned (as in the flip of a coin) to 1 of 2 study groups (the Combination group or the Sequential group). This is done because no one knows if one study group is better, the same, or worse than the other group.

Each study cycle is 4 weeks.

Combination Group:

If participant is assigned to the Combination Group, participant will receive 4 cycles of tremelimumab and durvalumab together, followed by 9 cycles of durvalumab alone.

If participant's disease gets worse at any point participant will begin a standard of care treatment chosen by the study doctor or participant will be given the option to enroll on another study. If participant receives a standard of care treatment, the study doctor will discuss the risks and procedures with participant in detail. If participant chooses to enroll on another study, a separate consent form will be provided and participant will be taken off this study.

Sequential Group:

If participant is assigned to the Sequential Group, participant will receive 4 cycles of tremelimumab alone, and then if the disease gets worse, participant will receive 9 cycles of durvalumab alone. The study doctor will discuss this with participant.

Study Drug Administration:

Each time participant receives tremelimumab or durvalumab, it will be given by vein over about 60 minutes on Day 1 of each cycle.

Length of Study:

Participant may receive the study drugs for up to 13 cycles.

If participant is in the combination group, participant may receive the standard of care treatment after the study drugs for as long as the doctor thinks it is in participant's best interest or until the disease get worse.

If participant is in the sequential group and participant completes the full 13 cycles of the study drugs without the disease getting worse, participant will have follow up visits until the disease gets worse or until participant begins receiving treatment on another study.

Participant will be taken off study if intolerable side effects occur, if participant is unable to follow study directions, or if the study doctor thinks it is in participant's best interest.

Study Visits:

Combination Group:

All visits will occur on Day 1 of each 28-day cycle.

On Day 1 of Cycles 1-13:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests, immune system testing, and to check the functioning of participant's thyroid during Cycles 1-6 only. If participant is able to become pregnant, the routine blood tests will include a pregnancy test during Cycles 1 and 3.

- Urine will be collected for routine tests.

- Participant will complete the same questionnaires participant did at screening. Participant will alternate among completing 7, 5, and 2 of the questionnaires each cycle.

During Cycle 1 only:

- Participant will return to the clinic for blood draws (1 tablespoon each time) for biomarker and immune system testing on Days 8, 15, and 22.

- Participant will have an EKG to check participant's heart function.

During Cycles 2, 4, 6, 8, 10, and 12 only, about 2 weeks after participant receives the study drugs, participant will have an MRI or a CT scan to check the status of the disease.

During Cycle 3 only, participant will have a core tumor biopsy for biomarker and immune system testing.

Participant may be asked to have 1 or 2 interviews at a point between Cycles 2 and 4 and/or Cycles 6 and 8. Participant may decline to take part in one or both of these interviews.

If the disease gets worse at any point participant will begin a standard of care treatment chosen by the study doctor or participant will be given the option to enroll on another study.

If the disease does not get worse after the 13 cycles of treatment with the study drugs, participant will enter a waiting period. If the disease gets worse during the waiting period, participant will then begin a standard of care treatment chosen by the study doctor or participant will be given the option to enroll on another study.

During the waiting period, the following tests and procedures will be performed after 30 days and then at every 2 months until participant begins the standard of care treatment chosen by participant's doctor or participant leaves the study:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the functioning of participant's thyroid.

- Urine will be collected for routine tests.

- Participant will complete the 7 questionnaires from screening.

If participant is receiving the standard of care treatment, participant will follow the same study visit schedule that participant did while receiving tremelimumab and durvalumab, except participant will not have the blood draws and biopsy for biomarker and immune system testing.

Sequential Group:

All visits will occur on Day 1 of each 28-day cycle.

On Day 1 of Cycles 1-4:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests, immune system testing, and to check the functioning of participant's thyroid. If participant is able to become pregnant, the routine blood tests will include a pregnancy test during Cycles 1 and 3.

- Urine will be collected for routine tests.

- Participant will complete the same questionnaires participant did at screening. Participant will alternate among completing 7, 5, and 2 of the questionnaires each cycle.

During Cycle 1 only:

- Participant will return to the clinic for blood draws (1 tablespoon each time) for biomarker and immune system testing on Days 8, 15, and 22.

- Participant will have an EKG to check participant's heart function.

During Cycles 2 and 4, only, about 2 weeks after participant receives the study drugs, participant will have an MRI or a CT scan to check the status of the disease.

Participant may be asked to have an interview between Cycles 2 and 4. Participant may decline to take part in this interview.

During Cycle 3 only, participant will have a core tumor biopsy for biomarker and immune system testing.

After Cycle 4 or if the disease gets worse, whichever occurs first, participant will wait at least 8 weeks to allow the tremelimumab to clear participant's system and then participant will receive up to 9 cycles of durvalumab only (Cycles 5-13).

About 1 month into the 8-week waiting period, participant will have a study visit. The following tests and procedures will be performed:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the functioning of participant's thyroid.

- Urine will be collected for routine tests.

- Participant will complete the 7 questionnaires from screening.

Participant will begin receiving durvalumab on Day 1 of Cycle 5.

On Day 1 of Cycles 5-13:

- Participant will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests and to check the functioning of participant's thyroid.

- Urine will be collected for routine tests.

- Participant will complete the same questionnaires participant did at screening. Participant will alternate between completing all 7 of the questionnaires and only 4 of the questionnaires each cycle.

During Cycle 5 only, participant will have an EKG to check participant's heart function.

During Cycles 5 and 6 only, an additional blood sample (about 1 tablespoon) will be drawn for immune system testing.

Participant may be asked to have an interview between Cycles 6 and 8. Participant may decline to take part in this interview.

During Cycles 6, 8, 10, and 12 only, about 2 weeks after participant receives the study drugs, participant will have an MRI or a CT scan to check the status of the disease.

End of Study Visit:

After participant has received participant's last dose of the study drugs or the standard of care treatment chosen by the study doctor, participant will have an end of study visit. The following tests and procedures will be performed:

- Participant will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and to check the functioning of participant's thyroid. If participant can become pregnant, part of this sample will be used for a pregnancy test.

- Urine will be collected for routine tests.

- Participant will complete the 7 questionnaires from screening.

Follow-up:

About 30 days and then every 2 months after participant's last dose of the study drugs or standard of care treatment:

- Participant will have a physical exam.

- Participant will have an MRI or a CT scan to check the status of the disease.

- Participant will complete 7 questionnaires (for the first 2 months only).

This is an investigational study. Neither durvalumab nor tremelimumab are FDA approved or commercially available for the types of cancer in this study. They are currently being used for research purposes only in these diseases. The study doctor can explain how the study drugs are designed to work.

Up to 115 participants will have screening tests to learn if they are eligible to take part in this study. Up to 100 participants that are found eligible will be enrolled in this study. All will take part at MD Anderson.

1 locations

United States (1)
  • University of Texas MD Anderson Cancer Center
    recruiting
    Houston, Texas, United States, 77030
Status:
recruiting
Type:
Interventional
Phase:
Start:
17 May, 2017
Updated:
18 May, 2017
Participants:
100
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