Description:
This phase I/II trial studies how well durvalumab works when given in combination with
carboplatin and paclitaxel in treating patients with stage III-IV ovarian, primary
peritoneal, or fallopian tube cancer. Immunotherapy with monoclonal antibodies, such as
durvalumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin
and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing
the cells, by stopping them from dividing, or by stopping them from spreading. Giving
durvalumab in combination with carboplatin and paclitaxel may be a better treatment for
ovarian, primary peritoneal, or fallopian tube cancer.
Title
- Brief Title: Matched Paired Pharmacodynamics and Feasibility Study of Durvalumab in Combination With Chemotherapy in Frontline Ovarian Cancer
- Official Title: Matched Paired Pharmacodynamics and Feasibility Study of Durvalumab in Combination With Chemotherapy in Frontline Ovarian Cancer
Clinical Trial IDs
- ORG STUDY ID:
2015-0900
- SECONDARY ID:
NCI-2016-00557
- NCT ID:
NCT02726997
Conditions
- Malignant Neoplasms of Female Genital Organs
- Ovarian Cancer
- Primary Peritoneal Carcinoma
- Fallopian Tube Cancer
Interventions
| Drug | Synonyms | Arms |
|---|
| Durvalumab | MEDI4736 | Durvalumab + Carboplatin + Paclitaxel |
| Carboplatin | Paraplatin | Durvalumab + Carboplatin + Paclitaxel |
| Paclitaxel | Taxol | Durvalumab + Carboplatin + Paclitaxel |
Purpose
The goal of this clinical research study is to learn about the safety of giving the
combination of MEDI4736 (durvalumab), carboplatin, and paclitaxel to patients with
high-grade epithelial non-mucinous ovarian, primary peritoneal, or fallopian tube cancer.
Researchers also want to learn how the study drug combination may affect DNA and RNA (the
genetic material in cells) and proteins.
Detailed Description
Study Groups:
This study has 2 parts: a safety lead-in and Phase 2.
If you are found to be eligible to take part in this study, you will be assigned to either
the Safety Lead-in or the Phase 2 portion, depending on when you join the study. Up to 12
participants will be enrolled in the Safety Lead-in, and up to 24 participants will be
enrolled in Phase 2.
If you are enrolled in the Safety Lead-in, the dose of durvalumab you receive will depend on
when you join this study. The first 4 participants will receive the first dose level of
durvalumab and be enrolled one at a time, every 3 weeks. Each new participant or group of up
to 6 participants enrolling after that will receive either the same dose as the previous
participant or group or a lower dose of either durvalumab or chemotherapy. This will
continue until a tolerable and appropriate dose of durvalumab and chemotherapy is found.
If you are enrolled in Phase 2, you will receive durvalumab at the highest dose that was
tolerated in the Safety Lead-in.
Study Drug Administration:
For all participants, the study drugs are given in 2 steps called Primary Therapy and
Maintenance.
In the Primary Therapy part of the study, each cycle is 21 days. You will receive the study
drugs on the schedule below for 3 cycles before and then 3 cycles after your planned surgery
(6 cycles total).
- You will receive paclitaxel by vein over 3 hours on Days 1, 8, and 15 of Cycles 1-6.
- You will receive carboplatin by vein over 1 hour on Day 1 of Cycles 1-6.
- You will receive durvalumab by vein over 1 hour every 2 weeks in Cycles 1-6.
After that, you may begin the Maintenance Phase. In this phase, cycles are 28 days long. You
will receive durvalumab alone every 2 weeks for 7 more cycles (28 weeks). It will continue
to be given by vein over 1 hour.
Study Visits during Primary Therapy:
At Week 1 of Cycles 1-6:
- You will have a physical exam.
- Blood (about 3 tablespoons) and urine will be collected for routine tests. In Cycles
1-3, this blood will also be used for biomarker tests. The biomarker tests in this
study may include genetic biomarkers. Biomarkers are found in the blood and tissue and
may be related to your reaction to the study drug.
- You will have an EKG to check your heart function (Cycles 1 and 6 only). In Cycle 1, an
EKG will be performed within 1 hour before the start of the study drug infusion and
then at least 1 more time in the 3 hours after the end of the infusion.
At Weeks 2 and 3 of Cycle 1:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine tests.
At Weeks 2 and 3 of Cycles 2-6, blood (about 3 tablespoons) will be drawn for routine tests.
After Cycle 3, you will temporarily stop receiving the study drugs as you prepare for the
surgery.
At your visit before surgery:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine and biomarker tests.
- You will have an EKG to check your heart function.
- You will have an MRI or CT scan to check the status of the disease.
You will sign a separate consent form for the surgery that explains the procedure and its
risks. During the surgery, tumor tissue will be collected for biomarker and genetic testing.
All samples will be stored at MD Anderson for an unlimited amount of time for testing
related to this study.
At your visit after surgery:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine tests.
At all visits during this part of the study except the day of surgery and the visit after
surgery, you will complete 1, 2, 5, or all 7 study questionnaires. You will be told how many
to complete each time. When you only complete 1 questionnaire at several of the visits, it
should take about 10-15 minutes.
Anytime the doctor thinks it is needed:
- If you can become pregnant, part of the routine blood sample will be used for a
pregnancy test.
- Part of the routine blood sample will be used for blood clotting tests.
Study Visits During Maintenance Therapy:
At Week 1 of Cycles 7-13:
- You will have a physical exam.
- Blood (about 1 tablespoon) and urine will be collected for routine tests.
- Blood (about 1 tablespoon) will be drawn for biomarker tests.
- You will have an EKG to check your heart function.
- You will complete 6 of the study questionnaires.
At Week 3 of Cycles 7-13:
- You will have a physical exam.
- Blood (about 1 tablespoon) will be drawn for routine tests.
Every 12 weeks, you will have an MRI or CT scan to check the status of the disease.
At every other visit during Cycles 7-12 and at Weeks 1 and 4 of Cycle 13, you will complete
1, 6, or all 7 study questionnaires. You will be told how many to complete each time.
Anytime the doctor thinks it is needed:
- If you can become pregnant, part of the routine blood sample will be used for a
pregnancy test.
- Part of the routine blood sample will be used for blood clotting tests.
Interviews:
You will have 2 interviews with the study staff: before you receive any treatment and after
you have completed at least 2 cycles of treatment before your tumor reduction surgery and
after you have begun receiving maintenance therapy with durvalumab alone. Each interview may
take 25-45 minutes.
During the interviews, you will be asked questions about any symptoms you had during the
time when you were diagnosed, symptoms you are currently having, and any symptoms you had
when you received previous treatments for cancer. During the second interview, you will be
asked how your symptoms have changed since the first interview.
The interviews will be held in a private conference room and will be digitally recorded. The
study staff will transcribe (create a text copy of) the interview and will not record your
name, medical record number, or any other identifying information. The electronic files and
transcription of the interview will be stored securely.
Length of Treatment:
You may receive up to 6 cycles of the study drug combination and up to 7 more cycles of
durvalumab alone. You will no longer be able to take the study drugs if the disease gets
worse, if intolerable side effects occur, or if you are unable to follow study directions.
Your participation on the study will be over after the follow-up.
End-of-Treatment Visi:
After your last study drug dose:
- You will have a physical exam.
- Blood (about 3 tablespoons) will be drawn for routine and biomarker tests.
- You will have an MRI or CT scan to check the status of the disease.
- You will have an EKG to check your heart function.
- You will complete 6 of the questionnaires.
Follow-up:
At 30 days after your last durvalumab dose:
- You will have a physical exam.
- Blood (about 2 tablespoons) will be collected for routine tests. If you can become
pregnant, part of this sample will be used for a pregnancy test.
- You will complete 6 of the questionnaires.
At Month 2 after your last durvalumab dose, blood (about 1 tablespoon) will be drawn for
routine tests.
At Month 3:
- You will have a physical exam.
- Blood (about 1 tablespoon) will be drawn for routine tests.
At Months 4, 6, 8, and 10, you will be asked how you are doing. This may also be done at
Month 9, depending on how long you took durvalumab and the reason you stopped it. The study
staff will tell you if you have this 9-month visit.
At the Month 12 and then every 6 months, depending on how long you took durvalumab and the
reason you stopped it, blood (about 3 tablespoons) may be drawn for routine tests.
As often as the doctor thinks is needed, you will have an MRI or CT scan to check the status
of the disease. This will depend on how long you took durvalumab and the reason you stopped
it.
If you choose not to return for follow-up visits, you can instead receive follow-up phone
calls at Months 2, 3, 4, 6, 8, and 10 after your last durvalumab dose and then every 2
months starting at Month 12. You will be asked how you are doing. The calls should take
about 10-15 minutes.
This is an investigational study. Durvalumab is not FDA approved or commercially available.
It is currently being used for research purposes only. Paclitaxel and carboplatin are FDA
approved and commercially available. The study doctor can explain how the study drugs are
designed to work.
Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Durvalumab + Carboplatin + Paclitaxel | Experimental | Phase I (Safety Lead-In): Participants receive Durvalumab, Carboplatin, and Paclitaxel at dose depending on when they join the study. Once maximum tolerated dose combination is reached Phase II portion of study begins.
Phase II: Participants receive Durvalumab, Carboplatin, and Paclitaxel at the maximum tolerated dose from Phase I for three, 21 day cycles. Interval debulking surgery is then performed followed by 3 more cycles of drug combination.
Maintenance Phase: Participants receive Durvalumab alone every 2 weeks for 7 more 28 day cycles.
Questionnaires completed about possible side effects, symptoms, quality of life, and satisfaction with care completed at baseline, week 1 of cycles 7 - 13 during Maintenance Phase, end of treatment visit, and at follow up visit 30 days after Durvalumab therapy. | - Durvalumab
- Carboplatin
- Paclitaxel
|
Eligibility Criteria
Inclusion Criteria:
1. Written informed consent and any locally-required authorization (e.g., Health
Information Portability and Accountability Act [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
2. Age >/= 18 years at time of study entry.
3. Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or
fallopian tube cancer.
4. No prior treatment for primary advanced (Stage III or IV) epithelial ovarian, primary
peritoneal, or fallopian tube carcinoma such as irradiation, chemotherapy, hormonal
therapy, immunotherapy, investigational therapy, surgery, and/or other concurrent
agents or therapies.
5. A disposition to neoadjuvant chemotherapy with planned interval tumor reductive
surgery after 3 complete cycles of treatment.
6. Planned chemotherapy with combination carboplatin and paclitaxel given intravenously.
7. Have measurable disease based on Response Evaluation Criteria In Solid Tumors
(RECIST) version 1.1. Measurable disease is defined as at least one 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, Computerized Tomography (CT), and Magnetic Resonance Imaging
(MRI), or >10 mm when measured by spiral CT.
8. Peripheral neuropathy Grade 0 or 1 by National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events (CTCAE) version 4.03.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
10. Life expectancy >/= 12 weeks.
11. Adequate normal organ and marrow function are defined as follows: Hemoglobin >/= 9.0
g/dL; Absolute neutrophil count (ANC) >/= 1.5 x 109/L (> 1500 per mm^3); Platelet
count >/= 100 x 109/L (>100,000 per mm^3); Serum bilirubin </= 1.5 x institutional
upper limit of normal (ULN); Aspartate Transaminase (AST) and Alanine Transaminase
(ALT) </= 2.5 x institutional upper limit of normal unless liver metastases are
present, in which case it must be </= 5x ULN; Serum creatinine Clearance (CL)>40
mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for
determination of creatinine CL--Creatinine CL (mL/min)=[Weight (kg) x
(140-Age)X0.85]/[72 x serum creatinine (mg/dL)].
12. Subjects must either be of non-reproductive potential (ie, 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.
13. 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 follow
up.
14. Pre-treatment tumor tissue available for research purposes. This tissue can be
collected from preoperative laparoscopy, other diagnostic biopsy, or a
research-specific biopsy. This pre-treatment tumor must be amenable to repeat tissue
sampling after induction therapy.
15. Signed informed consent on protocol LAB02-188
16. For participation in the Patient-reported Outcomes and Qualitative Interviews,
subjects must be fluent in English
Exclusion Criteria:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
2. Previous enrollment in the present study.
3. Prior treatment for ovarian, fallopian tube, or primary peritoneal cancer.
4. Histology showing mucinous or low grade epithelial carcinoma.
5. Participation in another clinical study with an investigational product during the
last 4 weeks.
6. Any previous treatment with a Programmed Cell Death Protein 1 (PD1) or PD-L1
inhibitor, including durvalumab.
7. 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 eg, cervical cancer in situ.
8. Mean QT interval corrected for heart rate (QTc) >/= 470 ms calculated from 3
electrocardiograms (ECGs) using Bazett's Correction.
9. Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, 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.
10. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. Any prior
Grade >/=3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE >Grade 1.
11. 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.
12. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
ulcerative colitis).
13. History of primary immunodeficiency.
14. History of allogeneic organ transplant.
15. History of hypersensitivity to durvalumab or any excipient.
16. History of hypersensitivity to paclitaxel or carboplatin or their excipients.
17. 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.
18. Known history of previous clinical diagnosis of tuberculosis.
19. History of leptomeningeal carcinomatosis.
20. Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab.
21. Female subjects who are pregnant/breast-feeding or who are of reproductive potential
and not employing acceptable methods of birth control. Acceptable methods of
contraception include true abstinence in line with the preferred and usual lifestyle
choice of the patient, tubal ligation, vasectomised partner, barrier methods (eg, cap
plus spermicide, sponge plus spermicide, diaphragm plus spermicide, or male condom
plus a spermicide), intrauterine device methods (eg, Copper T or
Levonorgestrel-releasing intrauterine system), or hormonal methods (eg, any
registered and marketed contraceptive agent that contains an estrogen and/or a
progestational agent) and that is administered via the oral, subcutaneous,
transdermal, intrauterine, or intramuscular route as an implant, hormone shot or
injection, combined pill, minipill or patch. All methods of contraception should be
used in combination with the use of a condom by their male sexual partner for
intercourse.
22. Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results.
23. Symptomatic or uncontrolled brain metastases requiring concurrent treatment,
inclusive of but not limited to surgery, radiation and/or corticosteroids.
24. Subjects with uncontrolled seizures.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using Paired T-Test |
| Time Frame: | 1 year |
| Safety Issue: | |
| Description: | Paired t-test with a 2-sided significance level of 0.05 used to test whether the change in biomarker expression from pre-treatment to post-treatment with Durvalumab is different from 0. |
Secondary Outcome Measures
| Measure: | Progression-Free Survival with Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer |
| Time Frame: | 1 year |
| Safety Issue: | |
| Description: | Progression defined by any of the following: 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids; significant increase in T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy not caused by comorbid events (eg, radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any new lesion; clear clinical deterioration not attributable to other causes apart from the tumor (eg, seizures, medication adverse events, complications of therapy, cerebrovascular events, infection) or changes in corticosteroid dose; failure to return for evaluation as a result of death or deteriorating condition; or clear progression of nonmeasurable disease. |
| Measure: | Feasibility of Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Determined by Methods of Thall et all |
| Time Frame: | 126 days |
| Safety Issue: | |
| Description: | Feasibility defined as the ability to complete all planned cycles of adjuvant therapy, using the methods of Thall et al. (1994). |
Details
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | M.D. Anderson Cancer Center |
Trial Keywords
- Malignant neoplasms of female genital organs
- Ovarian Cancer
- Primary Peritoneal Carcinoma
- Fallopian Tube Cancer
- High-grade epithelial non-mucinous ovarian cancer
- Laparoscopy surgery
- Durvalumab
- MEDI4736
- Carboplatin
- Paraplatin
- Paclitaxel
- Taxol
Last Updated
April 17, 2017
