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Matched Paired Pharmacodynamics and Feasibility Study of Durvalumab in Combination With Chemotherapy in Frontline Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT02726997
Recruitment Status : Recruiting
First Posted : April 4, 2016
Last Update Posted : September 13, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

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.

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.


Condition or disease Intervention/treatment Phase
Malignant Neoplasms of Female Genital Organs Ovarian Cancer Primary Peritoneal Carcinoma Fallopian Tube Cancer Drug: Durvalumab Drug: Carboplatin Drug: Paclitaxel Behavioral: Questionnaires Procedure: Debulking Surgery Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Matched Paired Pharmacodynamics and Feasibility Study of Durvalumab in Combination With Chemotherapy in Frontline Ovarian Cancer (N-Dur)
Actual Study Start Date : July 2016
Estimated Primary Completion Date : July 2021
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Experimental: Durvalumab + Carboplatin + Paclitaxel

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.

Drug: Durvalumab

Phase I (Safety Lead-In) Starting Dose: 750 mg by vein every two weeks in one, 21 day cycle

Phase II Starting Dose: 750 mg by vein every 2 weeks (pending confirmation in Phase I lead in) for three, 21 day cycles. After surgery, participants receive three more 21 day cycles.

Maintenance Phase: 750 mg by vein on Day 1 and Day 15 of each 28 day cycle for 7 cycles.

Other Name: MEDI4736

Drug: Carboplatin

Phase I (Safety Lead-In) Starting Dose: Area under curve (AUC) 6 by vein every three weeks in one, 21 day cycle.

Phase II Starting Dose: AUC 6 by vein on Day 1 every three weeks for 3, 21 day cycles. After surgery, participants receive three more 21 day cycles.

Other Name: Paraplatin

Drug: Paclitaxel

Phase I (Safety Lead-In) Starting Dose: 80 mg by vein every week in one, 21 day cycle.

Phase II Starting Dose: 80 mg by vein on Day 1, Day 8, and Day 15 for 3, 21 day cycles. After surgery, participants receive three more 21 day cycles.

Other Name: Taxol

Behavioral: Questionnaires
Questionnaires 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.
Other Name: Surveys

Procedure: Debulking Surgery
Surgery performed after three, 21 day cycles of study drug combination.
Other Name: Laparoscopy surgery




Primary Outcome Measures :
  1. 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 ]
    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.

  2. Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using an Exact Binomial Test [ Time Frame: 1 year ]
    Exact binomial test with a 1-sided significance level of 0.05 used to test whether the probability of a biomarker increasing (or decreasing) is > 0.50.

  3. Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer [ Time Frame: 1 year ]
    Fisher's exact test with a 1-sided significance level of 0.05 used to compare the proportion of participants treated with Durvalumab who have increasing (or decreasing) expression rates with the corresponding proportion from a historical control group of 30 untreated patients.

  4. Pharmacodynamic Changes Induced by Treatment with Durvalumab in Combination with Paclitaxel and Carboplatin in Women with Advanced Stage, Metastatic Ovarian Cancer Using a 2-Sample T-Test [ Time Frame: 1 year ]
    A 2-sample t-test with a 2-sided significance level of 0.05 used to compare change in biomarker expression between patients treated with Durvalumab and a control group of 30 untreated patients.


Secondary Outcome Measures :
  1. 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 ]
    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.

  2. 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 ]
    Feasibility defined as the ability to complete all planned cycles of adjuvant therapy, using the methods of Thall et al. (1994).



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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. a) 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. b) Patients with non-measurable but evaluable solid tumors may be deemed eligible contingent upon PI review. A non-measurable but evaluable solid tumor is defined as either unidimensionally measurable lesions, masses with margins not clearly defined, or lesions with maximal perpendicular diameters < 10mm that can still be evaluated for the primary endpoint.
  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.

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): NCT02726997


Contacts
Contact: Shannon Westin, MD 713-794-4314

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
AstraZeneca
Investigators
Principal Investigator: Shannon Westin, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02726997     History of Changes
Other Study ID Numbers: 2015-0900
NCI-2016-00557 ( Registry Identifier: NCI CTRP )
First Posted: April 4, 2016    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
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

Additional relevant MeSH terms:
Ovarian Neoplasms
Neoplasms, Glandular and Epithelial
Fallopian Tube Neoplasms
Neoplasms
Genital Neoplasms, Female
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Neoplasms by Histologic Type
Fallopian Tube Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs