Dactinomycin or Methotrexate in Treating Patients With Low-Risk Gestational Trophoblastic Neoplasia

Study Overview
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Brief Summary
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This randomized phase III trial studies how well methotrexate works compared to dactinomycin in treating patients with low-risk gestational trophoblastic neoplasia. Drugs used in chemotherapy, such as methotrexate and dactinomycin, 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. It is not yet known whether methotrexate is more effective than dactinomycin in treating gestational trophoblastic disease.

Detailed Description
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PRIMARY OBJECTIVES: I. To test the hypothesis that treatment with multi-day methotrexate is inferior to treatment with pulse actinomycin-D (dactinomycin) in patients with low-risk gestational trophoblastic disease with respect to complete response. SECONDARY OBJECTIVES: I. To describe the frequency of post protocol surgical treatment for each arm. II. To describe the frequency of post protocol multi-agent chemotherapy treatment for each arm. III. To compare multi-day methotrexate to actinomycin-D with respect to frequency and severity of adverse events in patients with low-risk gestational trophoblastic neoplasia. IV. To investigate the impact of treatment on overall quality-of-life (QOL) and explore the influence of treatment on issues such as body image, sexual functioning, and patient-reported side effects and disruption. V. To assess whether uterine artery pulsatility index (UAPI) can provide independent prognostic information predictive of single-drug resistance. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive dactinomycin intravenously (IV) over 15 minutes on day 1. ARM II: Patients receive methotrexate intramuscularly (IM) on days 1, 3, 5, and 7 and leucovorin calcium orally (PO) on days 2, 4, 6, and 8 OR single agent methotrexate IV on days 1-5. In both arms, treatment repeats every 14 days for up to 20 courses* in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up monthly for 1 year and then every 3 months for 1 year. NOTE: * Patients will be treated for three courses after human chorionic gonadotropin (hCG) < 5 mIU/mL or until evidence of treatment failure (biologic progression), disease progression, or unacceptable toxicity despite dose modifications. Upon normalization of hCG (< 5 mIU/mL), patients will be treated with three additional courses.

Official Title
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A Phase III Randomized Trial of Pulse Actinomycin-D Versus Multi-day Methotrexate for the Treatment of Low-Risk Gestational Trophoblastic Neoplasia

Conditions
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Choriocarcinoma, FIGO Stage I Gestational Trophoblastic Tumor, FIGO Stage II Gestational Trophoblastic Tumor, FIGO Stage III Gestational Trophoblastic Tumor, Hydatidiform Mole

Intervention / Treatment
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* Biological: Dactinomycin
* Drug: Leucovorin Calcium
* Drug: Methotrexate
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet International Federation of Gynecology and Obstetrics (FIGO) stage I, II, or III criteria for low-risk gestational trophoblastic neoplasia (GTN): post molar GTN or choriocarcinoma (as defined below); patients may have had a second curettage but must still meet GTN criteria below: Post molar GTN For the purposes of this study, patients must have undergone evacuation of a complete or partial hydatidiform mole and then meet the criteria for GTN defined as: A < 10% decrease in the hCG level using as a reference the first value in the series of 4 values taken over a period of 3 weeks (> 50 mIU/ml minimum) OR A > 20% sustained rise in the hCG taking as a reference the first value in the series of 3 values taken over a period of 2 weeks (> 50 mIU/ml minimum) OR A persistently elevated hCG level a period of 6 months or more following the initial curettage (> 50 mIU/ml minimum) Choriocarcinoma Histologically proven non-metastatic choriocarcinoma OR Histologically proven metastatic choriocarcinoma if the metastatic site(s) is restricted to one (or more) of the following: vagina, parametrium, or lung World Health Organization (WHO) risk score 0-6 Patients must be willing to practice effective contraception for the duration of the study White blood cell count (WBC) >= 3,000 cells/mcL Granulocytes >= 1,500/mcL Platelets >= 100,000/mcL Creatinine =< 2.0 mg/dcL Bilirubin =< 1.5 x institutional normal Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x institutional normal Alkaline phosphatase =< 3 x institutional normal Patients who have met the pre-entry requirements Before enrolling a patient, the institution must verify the availability of an adequate supply of methotrexate for a full course of therapy Patients must have signed an approved informed consent and authorization permitting release of personal health information Exclusion Criteria: Patients who do not have GTN Patients with non-gestational choriocarcinoma Patients who have previously been treated with cytotoxic chemotherapy; however, patients who received prior low-dose methotrexate for treatment of an ectopic pregnancy will be eligible for this study Patients who have received prior pelvic radiation Patients with placental-site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT) Patients with Gynecologic Oncology Group (GOG) performance status of 3 or 4 Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy Patients whose circumstances at the time of study entry do not permit completion of the study or required follow-up Patients who wish to breast-feed during treatment

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 I (dactinomcin)<br>Patients receive dactinomycin IV over 15 minutes on day 1. | Biological: Dactinomycin<br>* Given IV<br>* Other names: Meractinomycin;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Active Comparator: Arm II (leucovorin calcium and methotrexate)<br>Patients receive methotrexate IM on days 1, 3, 5, and 7 and leucovorin calcium PO on days 2, 4, 6, and 8 OR single agent methotrexate IV on days 1-5. | Drug: Leucovorin Calcium<br>* Given PO<br>* Other names: Wellcovorin;Drug: Methotrexate<br>* Given IV and IM<br>* Other names: WR-19039;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response | Complete Response is defined as 3 consecutive bi-weekly values of hCG<5 over a minimum of 4 weeks of normal hCG values with no values greater than 5 mIU/ml | hCG testing is performed prior to each cycle to treatment until treatment is completed, up to 10 months. For patients who have responded to treatment hCG must be obtained every 4 weeks for 1 year after completing treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With CTCAE v4 Graded Adverse Events With Low-risk Gestational Trophoblastic Neoplasia by Arm | Maximum grade of physician assessed adverse events reported during treatment | Assessed throughout the treatment period and within 2-4 weeks after discontinuation of treatment | 
| The Number of Participants With Post Protocol Surgical Treatment for Each Arm. |  | Anytime during post treatment follow-up for up to 2 years from study entry. | 
| The Number of Participants With Post Protocol Multi-agent Chemotherapy Treatment for Each Arm. |  | Anytime during post treatment follow-up for up to 2 years from study entry. | 
| Patient-reported Quality of Life (QOL) at Baseline | Patient reported quality of life was measured with the Functional Assessment of Cancer Therapy - Generic (FACT-G). The FACT-G is a scale for assessing general QOL of cancer patients. It consists of four subscales: Physical Well Being, Functional Well Being, Social/Family Well-Being, and Emotional Well-Being. Each item in the FACT-G was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative statements, reversal was performed prior to score calculation. According to the FACIT measurement system, a subscale score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the subscale. The FACT-G score is calculated as the sum of the subscale scores. The FACT-G score ranges 0-108. A larger score suggests better QOL. | Prior to cycle 1 | 
| Patient-reported Quality of Life (QOL) After Baseline Visit. | Patient reported quality of life was measured with the Functional Assessment of Cancer Therapy - Generic (FACT-G). The FACT-G is a scale for assessing general QOL of cancer patients. It consists of four subscales: Physical Well Being, Functional Well Being, Social/Family Well-Being, and Emotional Well-Being. Each item in the FACT-G was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). For the negative statements, reversal was performed prior to score calculation. According to the FACIT measurement system, a subscale score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the subscale. The FACT-G score is calculated as the sum of the subscale scores. The FACT-G score ranges 0-108. A larger score suggests better QOL. | Prior to cycle 3 (4 weeks after cycle 1 if off study treatment prior to cycle 3). Prior to cycle 5, Prior to cycle 7, 26 weeks after starting study treatment. |