Avatar-Directed Chemotherapy in Treating Patients With Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well Avatar-directed chemotherapy works in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that does not respond to platinum anti-cancer drugs. Drugs used in chemotherapy, such as paclitaxel, gemcitabine hydrochloride, pegylated liposomal doxorubicin hydrochloride, topotecan hydrochloride, 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. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Using an Avatar, a living tumor sample with similar genetic characteristics to the original tumor, may help determine which chemotherapy is most effective.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the response rate of Avatar-directed salvage chemotherapy in patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers. SECONDARY OBJECTIVES: I. To determine the progression-free survival of patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-directed salvage chemotherapy. II. To determine the overall survival of patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-directed salvage chemotherapy. III. To determine the adverse events for patients with platinum-resistant ovarian, primary peritoneal and fallopian tube cancers receiving Avatar-directed salvage chemotherapy. IV. To determine the correlation between patient response and response in their Avatar. V. To enrich the Avatar response signature in response to Avatar-directed therapy using patient outcomes. VI. To compare the response rates between patients who did or did not receive bevacizumab treatment. OUTLINE: Patients are assigned to 1 of 4 treatment arms as directed by Avatar results. ARM A: Patients receive paclitaxel intravenously (IV) over 1-96 hours on days 1, 8, and 15. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity ARM B: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 every 21 days or days 1, 8, and 15 every 28 days. Patients may also receive bevacizumab IV over 90 minutes on day 1 every 21 days or days 1 and 15 every 28 days. Courses repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3-6 months for 3 years.

Official Title
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Avatar-Directed Chemotherapy in Platinum-Resistant Ovarian, Primary Peritoneal and Fallopian Tube Cancers

Conditions
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Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Gemcitabine Hydrochloride
* Drug: Paclitaxel
* Drug: Pegylated Liposomal Doxorubicin Hydrochloride
* Drug: Topotecan Hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic confirmation of ovarian, primary peritoneal or fallopian tube cancer of any subtype Prior consent to have tumors used for unspecified future research Ability to provide written informed consent Willing to agree to periodic contact with a member of the study team during the period that the cancer has not recurred and/or has not become platinum resistant Willing to agree that the local medical oncologist may be informed that patient has agreed to participate in the study Platinum resistant or refractory ovarian, primary peritoneal or fallopian tube cancer of any subtype; Note: platinum-sensitive disease is allowed in cases where there is a contraindication to platinum-based therapy (i.e., allergy to platinum); this must be reviewed and approved by the Principal Investigator Successful Avatar engraftment with successful expansion and treatment outcome of Avatar therapy Eastern Cooperative Oncology Group (ECOG) performance status (ECOG performance status [PS]) of 0, 1 or 2 Measurable disease or non-measurable disease; for patients with non-measureable disease, they must also have a cancer antigen (CA)-125 measurement of > 35 U/mL or 2 X their documented nadir on 2 separate measurements 1 week apart The following laboratory values obtained =< 21 days prior to registration; complete blood count (CBC), sodium, potassium, aspartate aminotransferase (AST), bilirubin and creatinine are to be obtained pre-study; Note: treatment initiation and dosing modification should be performed at the individual investigators discretion and be consistent with the product label and their medical practice Negative urine or serum pregnancy test performed =< 7 days prior to registration, for women of child bearing potential only Willing to return to enrolling institution for follow-up or have a local physician willing to submit response and outcome data; Note: any and all therapy, potentially in its entirety, may be conducted outside of the Mayo Clinic Exclusion Criteria: Any of the following: Pregnant women Nursing women Prior treatment with Doxil, topotecan, Gemzar or Taxol chemotherapy for platinum-resistant cancer; Note: Allowed prior therapy with Doxil or Gemzar if given for platinum sensitive disease in combination with a platinum drug AND the Avatar data indicates a drug other than Doxil or Gemzar would be effective; Note: Allowed prior therapies for patients following confirmation of platinum-resistant cancer include: Therapeutic antibodies, such as bevacizumab Small molecule kinase inhibitors, such as pazopanib Vaccines and immunotherapy All of these exceptions should be confirmed with the Principal Investigator (PI) prior to registration Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; Note: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial Uncontrolled intercurrent illness judged by the treating investigator to preclude treatment with chemotherapy Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving treatment for their cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Avatar-directed paclitaxel)<br>Patients receive paclitaxel IV over 1-96 hours on days 1, 8, and 15. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;|
| Experimental: Arm B (Avatar-directed gemcitabine hydrochloride)<br>Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;|
| Experimental: Arm C (Avatar-directed liposomal doxorubicin)<br>Patients receive pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1. Patients may also receive bevacizumab IV over 90 minutes on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Pegylated Liposomal Doxorubicin Hydrochloride<br>* Given IV<br>* Other names: TLC D-99;|
| Experimental: Arm D (Avatar-directed topotecan hydrochloride)<br>Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 every 21 days or days 1, 8, and 15 every 28 days. Patients may also receive bevacizumab IV over 90 minutes on day 1 every 21 days or days 1 and 15 every 28 days. Courses repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Topotecan Hydrochloride<br>* Given IV<br>* Other names: topotecan hydrochloride (oral);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a confirmed tumor response, defined as complete response or partial response estimated using Response Evaluation Criteria in Solid Tumors 1.1 criteria | Estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the exact Binomial method. The primary analysis will pool across all patients, and tumor response rate by treatment arm will also be looked at in an exploratory fashion. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AE) | Maximum grade for each type of AE will be recorded for each patient, and frequency tables will be reviewed to determine AE patterns. | Up to 3 years | 
| Overall survival (OS) | OS will be estimated using the method of Kaplan-Meier. | Time from registration to death from any cause, assessed up to 3 years | 
| Progression free survival (PFS) | PFS will be estimated using the method of Kaplan-Meier. | Time from registration to the first of either disease progression or death from any cause, assessed up to 3 years | 
| Response rates | The Chi-square or Fisher's Exact test will be used to compare the response rates between patients who did or did not receive bevacizumab treatment. The response rates will also be reported by treatment type (bevacizumab or no bevacizumab). | Up to 3 years |