A Randomized Phase II Induction Discontinuation Trial of Emactuzumab following Paclitaxel and Bevacizumab in Patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer
You are being asked to take part in this study because you have ovarian, fallopian tube, or primary peritoneal cancer that is relapsed (has come back) or refractory (has not responded to treatment). 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.
Disease Group: Malignant neoplasms of female genital organs
Treatment Agent: Bevacizumab,Emactuzumab,Paclitaxel
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Gateway for Cancer Research,Genentech Pharmaceuticals,Moonshots Program,Roche,The V Foundation for Cancer Research
Primary Part 1: To evaluate the safety of administration of paclitaxel, bevacizumab and emactuzumab over 4 weeks. Part 2B: To compare the progression-free survival (PFS) of patients with stable disease following Part 2A randomized to paclitaxel plus bevacizumab or to paclitaxel, bevacizumab plus emactuzumab. Secondary To estimate the progression-free survival (PFS) of the treatment arms. Objective response rate (ORR) by RECIST and CA-125 response criteria (“responders”). by RECIST only (“RECIST responders”). by CA-125 response criteria only (“CA-125 responders”). Biological progression-free interval (PFIbio) by serum CA-125 assessed according to the GCIG criteria ( http://www.gcig.igcs.org/CA-125.html ). Overall survival (OS). Safety and tolerability. To characterize the pharmacokinetics of bevacizumab and emactuzumab when administered in combination. Exploratory To assess the utility of surrogate biomarkers and the anti-tumor response to therapy with the combination treatment of bevacizumab and emactuzumab, we will draw 20 ml blood for plasma markers (VEGF, VEGFR, IL6, IL8, FGF, PDGFAA, CSF1, and IL34) and other chemokines identified by secretome proteomics) and potential exosomal markers (M2-like markers VEGFR1-3, CD11b +CD68, CD11b+CD14/CD15/CD33, CD11b+CD11c, MHCII), prior to initiation of paclitaxel/bevacizumab/emactuzumab and after pre-infusion every 4 weeks for the patient safety lead-in (Part 1), and randomized therapy (Part 2B). In Part 2, we will seek to obtain 2 biopsies, one pre-treatment tissue biopsy prior to initiation of Part 2A and one pre-randomization tissue biopsy prior to initiation of Part 2B. These biopsied tissues will be used for monitoring dynamic changes in adapted macrophages (with phenotype of M2-like: VEGFR1-3+, CD markers (e.g. +CD68, CD163+), CSF1/CSF1R+ and MHCIIlow), and hypoxia markers as well as CD4/CD8, NK, and T-reg. If a third biopsy is obtained (following progression) we will run a third set of tissue biomarkers. In addition, we will also evaluate other molecular pathways (e.g., epigenetic modifications). To assess tumor alterations by serial non-invasive imaging macrophage-specific imaging, ADC (Apparent Diffusion Coefficient) for cellularity, and DCE (Dynamic Contrast Enhanced) for vasculature.
IRB Review and Approval Date: 05/05/2017
Recruitment Status: Open
Projected Accrual: 121
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 (+ 7 days). The date should be calculated from the last administered dose of platinum therapy).
5) 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. Part 1: Patients must have have one or more measurable target lesion. Part 2: 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.
1) Patients who have disease progression prior to completion of intended
frontline therapy, including patients demonstrating disease progression
after interval cytoreduction.
2) Non-epithelial, including malignant mixed Müllerian tumors.
3) Ovarian tumors with low malignant potential (i.e. borderline tumors).
4) For Part 2 patients only: 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 for ovarian cancer.
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 surgica, 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.
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
Information and next steps
Malignant neoplasms of female genital organs
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