Patient case: 26-year-old female with Cervical cancer. Genetic variant: STK11. Other conditions: None.

Clinical trial: Induction Discontinuation Trial of Emactuzumab Following Paclitaxel and Bevacizumab in Patients With Platinum-Resistant, Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer - REDIRECT

Summary: The goal of this clinical research study is to learn if adding emactuzumab to the combination of paclitaxel and bevacizumab can help to control relapsed or refractory ovarian, Fallopian tube, or primary peritoneal cancer. The safety and side effects of this drug combination will also be studied.

Detailed description: Part 1:
  Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join the study. Up to 9 participants will be enrolled in Part 1 of the study, and up to 112 participants will be enrolled in Part 2.
  You are in Part 1, you will receive paclitaxel, bevacizumab, and emactuzumab to check for the highest tolerable dose.
  Study Drug Administration:
  Every study cycle will be 28 days.
  You will receive paclitaxel by vein over 1 hour on Days 1, 8, 15, and 22, of each cycle. You will receive bevacizumab and emactuzumab by vein on Days 1 and 15 of each cycle. Bevacizumab will be given over about 90 minutes the first time it is given. Doses after this will be given over a shorter time if no side effects are seen. Emactuzumab will be given over about 30 minutes each time it is given on this study.
  If the disease gets worse and you agree, you will have a core biopsy, be taken off study, and offered other treatment options.
  Length of Study:
  You may continue receiving the study drugs for as long as the doctor thinks it is in your best interest. 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.
  Study Visits:
  On Day 1 of every cycle:
  -  You will have a physical exam.
  -  Blood (about 2½ tablespoons) will be drawn for routine testing, to check your, heart function, and for tumor marker testing.
  -  Urine will be collected for routine tests.
  -  Blood (about 1 teaspoon each time) will be drawn before and after the dose for pharmacokinetic (PK) testing. PK testing measures how much study drug is in the body at different time points.
  On Day 1 of Cycle 2 and every 8 weeks after that, you will have either a CT or MRI of the chest, abdomen, and pelvis.
  On Days 8, 15, and 22 of every cycle, blood (about 2 tablespoons) will be drawn for routine tests.
  Day 1 of Cycles 1, 3, and 5, blood (about 1 teaspoon) will be drawn before the dose for pharmacodynamic (PD) biomarker testing. PD testing measures how the level of study drug in your body may affect the disease.
  If the doctor thinks it is needed, you may have an EKG at any time during the study.
  End of Treatment:
  After you stop receiving the study drugs, the following tests and procedures will be performed:
  -  You will have a physical exam.
  -  Blood (about 2 ½ tablespoons) will be drawn for routine tests, to check your heart function, and for tumor marker testing.
  -  Urine will be collected for routine tests.
  -  You will have either a CT or MRI of the chest, abdomen, and pelvis.
  -  Blood (about 1 teaspoon) will be drawn for PD testing.
  Follow-Up Visit:
  About 30 days (+/- 5 days) after receiving your last dose of study drugs:
  -  You will have a physical exam.
  -  Blood (about 2 ½ tablespoons) will be drawn for routine and tumor marker testing.
  Information about your health status will continue to be collected from your medical record for up to 5 years after you leave the study.
  This is an investigational study. Bevacizumab and paclitaxel are FDA approved and commercially available for the treatment of several types of cancer. This drug combination is approved for the treatment of epithelial ovarian, primary peritoneal, and fallopian tube cancer. Emactuzumab is not FDA approved or commercially available. The addition of emactuzumab to the combination of bevacizumab and paclitaxel is investigational and is currently being used for research purposes only. The doctor can explain how the study drugs are designed to work.
  Up to 9 participants will be enrolled in Part 1 of this multicenter study. All will take part at MD Anderson.
  Up to 112 participants will be enrolled in Part 2 of this study. Up to 74 will take part at MD Anderson.
  Part 2:
  Study Groups:
  If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join the study. Up to 9 participants will be enrolled in Part 1 of the study, and up to 112 participants will be enrolled in Part 2.
  You are in Part 2.
  You will begin the study by receiving paclitaxel and bevacizumab for up to 8 weeks. After that, you will be randomly assigned (as in the flip of a coin) to 1 of 2 study arms.
  -  If you are in Arm 1, you will receive paclitaxel and bevacizumab.
  -  If you are in Arm 2, you will receive paclitaxel, bevacizumab, and emactuzumab.
  Study Drug Administration:
  Every study cycle will be 28 days.
  You will receive paclitaxel by vein over about 1 hour on Days 1, 8, 15 and 22 for up to 2 cycles and you will receive bevacizumab by vein on Days 1 and 15 for up to 2 cycles. This will be called Part 2A. The status of the disease will then be checked.
  If the disease gets worse and you agree, you will have a core biopsy, be taken off study, and offered other treatment options. If the disease improves, you will continue to receive the same treatment as in Part 2A and will not continue onto Part 2B. If the disease is stable, you will have a core biopsy and continue onto Part 2B.
  -  If you are in Arm 1 of Part 2B, you will receive paclitaxel by vein over 1 hour on Days 1, 8, 15, and 22 of each cycle and you will receive bevacizumab by vein on Days 1 and 15 of each cycle.
  -  If you are in Arm 2 of Part 2B, you will receive paclitaxel by vein over 1 hour on Days 1, 8, 15, and 22 of each cycle and you will receive bevacizumab and emactuzumab by vein on Days 1 and 15 of each cycle.
  Length of Study:
  You may continue receiving the study drugs for as long as the doctor thinks it is in your best interest. 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.
  Study Visits:
  On Day 1 of every cycle:
  -  You will have a physical exam.
  -  Blood (about 2½ tablespoons) will be drawn for routine testing, to check your, heart function, and for tumor marker testing.
  -  Urine will be collected for routine tests.
  -  If you are in Part 2B, blood (about 1 teaspoon each time) will be drawn before and after the dose for pharmacokinetic (PK) testing. PK testing measures how much study drug is in the body at different time points.
  On Day 1 of Cycle 2 and every 8 weeks after that, you will have either a CT or MRI of the chest, abdomen, and pelvis.
  On Days 8, 15, and 22 of every cycle, blood (about 2 tablespoons) will be drawn for routine tests.
  If you are in Part 2A, on Day 22 of Cycle 2, blood (about 1 teaspoon) will be drawn before the dose for PD testing.
  If you are in Part 2B, on Day 1 of Cycles 3 and 5, blood (about 1 teaspoon) will be drawn before the dose for PD testing.
  If the doctor thinks it is needed, you may have an EKG at any time during the study.
  End of Treatment:
  After you stop receiving the study drugs, the following tests and procedures will be performed:
  -  You will have a physical exam.
  -  Blood (about 2 ½ tablespoons) will be drawn for routine tests, to check your heart function, and for tumor marker testing.
  -  Urine will be collected for routine tests.
  -  You will have either a CT or MRI of the chest, abdomen, and pelvis.
  -  If you are in Part 2B, blood (about 1 teaspoon) will be drawn for PD testing.
  Follow-Up Visit:
  About 30 days (+/- 5 days) after receiving your last dose of study drugs:
  -  You will have a physical exam.
  -  Blood (about 2 ½ tablespoons) will be drawn for routine and tumor marker testing.
  Information about your health status will continue to be collected from your medical record for up to 5 years after you leave the study.
  This is an investigational study. Bevacizumab and paclitaxel are FDA approved and commercially available for the treatment of several types of cancer. This drug combination is approved for the treatment of epithelial ovarian, primary peritoneal, and Fallopian tube cancer. Emactuzumab is not FDA approved or commercially available. The addition of emactuzumab to the combination of bevacizumab and paclitaxel is investigational and is currently being used for research purposes only. The doctor can explain how the study drugs are designed to work.
  Up to 9 participants will be enrolled in Part 1 of this multicenter study. All will take part at MD Anderson.
  Up to 112 participants will be enrolled in Part 2 of this study. Up to 74 will take part at MD Anderson.

Eligibility: Inclusion Criteria:
  1. Signed informed consent obtained prior to initiation of any study-specific procedures and treatment as confirmation of the patient's awareness and willingness to comply with the study requirements (inclusive of 2 biopsies, one at baseline and if they qualify, one pre-randomization for part 2B).
  2. Women 18 years of age or older.
  3. Histologically confirmed and documented disease to include: adenocarcinoma NOS (Not Otherwise Specified), clear cell adenocarcinoma, endometrioid adenocarcinoma, malignant Brenner's tumor, mixed epithelial carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, transitional cell carcinoma, and undifferentiated carcinoma.
  4. Patients must have platinum-resistant disease, (defined as progression within <6 months from completion of a minimum of 4 platinum therapy cycles. The date should be calculated from the last administered dose of platinum therapy).
  5. Patients must have disease that is measurable according to RECIST 1.1 or assessable according to the GCIG CA-125 criteria and require chemotherapy treatment. Patients must have two or more measurable target lesions. a. Measurable disease is defined 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, CT, and MRI, or >/= 10 mm when measured by spiral CT.
  6. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  7. Newly obtained core or excisional biopsy of a tumor lesion for Part 2A and if they qualify, one pre-randomization biopsy for part 2B.
  8. Adequate organ function as determined by the following laboratory values: a. Absolute neutrophil count >/=1,500 /mcL. b. Platelets >/=100,000 / mcL c. Hemoglobin >/=9 g/dL or >/=5.6 mmol/L. d. Creatinine Clearance >/=60 mL/min for subject with creatinine levels > 1.5 X institutional ULN. e. Total Bilirubin </= 1.5 X ULN OR Direct bilirubin </= ULN for subjects with total bilirubin levels > 1.5 ULN. f. AST (SGOT) and ALT (SGPT) </= 2.5 X ULN OR </= 5 X ULN for subjects with liver metastases. g. INR/PT </=1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants). h. PTT </=1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
  9. Life expectancy of >/= 12 weeks.
  Exclusion Criteria:
  1. Patients whose disease was refractory to their previous platinum treatment. Refractory disease is defined as those patients who progressed during the preceding platinum treatment.
  2. Non-epithelial, including malignant mixed Müllerian tumors.
  3. Ovarian tumors with low malignant potential (i.e. borderline tumors).
  4. History of other clinically active malignancy within 5 years of enrollment, except for tumors with a negligible risk for metastasis or death, such as adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix or breast, or early stage endometrial cancer (stage IA/B, Grade 1 or 2, endometrioid histology).
  5. Previous treatment with >2 anticancer regimens.
  6. Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment, with the following exceptions: - Hormone-replacement therapy or oral contraceptives - Tyrosine kinase inhibitors (TKIs) that have been discontinued > 7 days prior to Cycle 1, Day 1; screening scans must be obtained after discontinuation of prior TKIs.
  7. Any prior radiotherapy to the pelvis or abdomen.
  8. Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study. Minor surgical procedures including placement of a vascular access device, within 2 days of the first study treatment.
  9. Previous exposure to murine CA-125 antibody (only applicable to those patients with non-measurable disease by RECIST).
  10. Current or recent (within 10 days prior to the first study drug dose) chronic daily treatment with aspirin (>325 mg/day).
  11. Current or recent treatment with another investigational drug within 30 days of first study treat¬ment dosing or earlier participation in this study.
  12. Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to Cycle 1, Day 1. Patients who have received acute and/or lowrolment, or anticipation of need for major surgical, a one-time dose of dexamethasone for nausea or chronic use of </= 10 mg/day of prednisone or dose-equivalent corticosteroid) may be enrolled in the study after discussion with and approval by the Medical Monitor. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed. Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drug.
  13. Received therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
  14. Patients with urine dipstick for proteinuria >2+. Patients with >/=2+ proteinuria on baseline dipstick analysis should undergo a 24-hour urine collection and must demonstrate </=1 g of protein in the 24-hour urine. Alternatively, proteinuria testing can be performed according to local standards.
  15. Patients with known auto-immune disease.
  16. Patients with known history of HIV, HBV and HCV infection.
  17. Patient has received an organ transplant.
  18. Patient has a history of hematological malignancy within the last 5 years prior to study entry. Prior allogenic bone marrow transplantation or prior solid organ transplantation.
  19. History of or active autoimmune disease including, but not limited to, systemic lupus erythematous, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, and vasculitis or glomerulonephritis. Patients with autoimmune thyroid disease on a stable thyroid replacement regimen; controlled vitiligo, eczema, psoriasis, or seborrhoic dermatitis with only dermatologic manifestations; or controlled Type I diabetes on a stable insulin regimen may be eligible for the study with approval by the Medical Monitor.
  20. History or evidence upon physical / neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).
  21. Symptomatic CNS metastasis.
  22. Pre-existing peripheral neuropathy >/= CTC grade 2 for those patients who received prior paclitaxel.
  23. Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >/= 2 weeks prior to screening.
  24. Increased corrected QT (QTc) interval (QTc > 470 ms), patients with baseline resting bradycardia < 45 bpm, or baseline resting tachycardia > 100 bpm.
  25. Family history of long QT syndrome or other risk factors for torsades de pointes, and/or the use of concomitant medications that prolong the QT/QTc interval.
  26. Signs or symptoms of serious active infection requiring oral or i.v. antibiotics within 2 weeks prior to Cycle 1 Day 1 and/or hospitalization at study entry including, but not limited to, hospitalization for complications of infection, bacteremia, active tuberculosis or severe pneumonia..
  27. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days (with a confirmatory urine pregnancy test within 7 days prior to study treatment start).
  28. For women who are not postmenopausal (<12 months of non therapy-induced amenorrhea, with no identified cause other than menopause) and have not undergone surgical sterilization (removal of ovaries and/or uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or use two adequate non hormonal methods of contraception, including at least one method with a failure rate of <1% per year, during the treatment period and for at least 4 months after the last dose of study drug.
  29. Continued from above: Examples of non-hormonal contraceptive methods with a failure rate of <1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  30. History or evidence of thrombotic or hemorrhagic disorders; including cerebrovascular accident (CVA) / stroke or transient ischemic attack (TIA) or sub-arachnoid hemorrhage within </=6 months prior to the first study treatment.
  31. Uncontrolled hypertension (sustained systolic >150 mmHg and/or diastolic >100 mmHg despite antihypertensive therapy) or clinically significant (i.e. active) cardiovascular disease, including: - myocardial infarction or unstable angina within </=6 months prior to the first study treatment. - New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF). -serious cardiac arrhythmia requiring medication (with the exception of atrial fibrillation or paroxysmal supraventricular tachycardia). - Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior of study enrollment. - Prior history of hypertensive crisis or hypertensive encephalopathy.
  32. History of bowel obstruction, including sub-occlusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess. Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.
  33. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
  34. History of hemoptysis (>/= 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment for any tumor type.
  35. Non-healing wound, ulcer or bone fracture.
  36. Known hypersensitivity to any of the study drugs or excipients.
  37. Evidence of any other medical conditions (such as psychiatric illness, peptic ulcer, etc.), physical examination or laboratory findings that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.

Relevance to patient case: not relevant