Natural Progesterone for the Treatment of Recurrent Glioblastoma

Study Overview
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Brief Summary
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This early phase I trial identifies the best dose, possible benefits and/or side effects of natural progesterone in treating patients with glioblastoma that has come back (recurrent). Progesterone is a type of hormone made by the body that plays a role in the menstrual cycle and pregnancy. Progesterone may help control tumor growth and spread in patients with glioblastoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine that the pharmacokinetics of natural progesterone given to recurrent glioblastoma [GBM] patients by subcutaneous injection is consistent with previous determinations made given subcutaneously using the aqueous formulation of progesterone. II. To determine the safety of administering daily subcutaneous natural progesterone for the treatment of patients with recurrent GBMs. III. To determine the rate of stable disease (SD) or better (partial response [PR] or complete response [CR]) at 8 weeks in eligible patients with recurrent GBM treated with daily subcutaneous natural progesterone. SECONDARY OBJECTIVES: I. To determine and compare the progression free survival of eligible patients with recurrent GBM compared with matched historical controls treated with a range of standard therapies. II. To determine and compare the overall survival of eligible patients with recurrent GBM compared with matched historical controls treated with a range of standard therapies. EXPLORATORY OBJECTIVES: I. To determine whether progesterone receptor levels within the tumor correlates with response to daily subcutaneous natural progesterone. II. To determine if other intrinsic tumor factors (mutations and genomic loss/gains) correlates with response to daily subcutaneous natural progesterone. III. To determine if the absolute values or changes in the level of serum biomarkers correlates with response to daily subcutaneous natural progesterone. IV. To determine the quality-of-life (QOL) by validated instruments of eligible patients with recurrent GBM treated with daily subcutaneous natural progesterone and assess whether this differs from historical controls. OUTLINE: Patients receive progesterone subcutaneously (SC) once daily (QD) for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

Official Title
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Pilot Study of Subcutaneously Administered Natural Progesterone for the Treatment of Recurrent GBM

Conditions
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Gliosarcoma, Recurrent Glioblastoma

Intervention / Treatment
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* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Biological: Therapeutic Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have pathologic confirmation of a glioblastoma or gliosarcoma diagnosis at initial surgery or second or later surgery Patients may have had up to two previous salvage agents administered for treatment of recurrent GBM (may be at 1st, 2nd or 3rd recurrence) Patients must be >= 18 years of age Patients must be able to have magnetic resonance imaging (MRI) scans for disease follow up Recurrent GBM must consist of a minimum of 1 cm^3 of contrast enhancing disease on high resolution T1 post-contrast sequence as defined on pre-treatment MRI obtained within 14 days of initiating therapy White blood cell (WBC) >= 3,000/uL (=< 14 days prior to registration) Absolute neutrophil count (ANC) >= 1,500/uL (=< 14 days prior to registration) Platelet count of >= 75,000/uL (=< 14 days prior to registration) Hemoglobin >= 9.0 gm/dl (=< 14 days prior to registration) (transfusion is allowed to reach minimum level) Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) =< 2.0 x upper limit of normal (UNL) (=< 14 days prior to registration) Bilirubin =< 2 x UNL (=< 14 days prior to registration) Creatinine =< 1.5 mg/dL (=< 14 days prior to registration) Patients must have a life expectancy of >= 12 weeks Patients must have a Karnofsky Performance Status (KPS) >= 60 Patients who are women of childbearing potential must have a negative pregnancy test documented =< 14 days prior to registration and agree to use adequate barrier contraceptive methods or abstinence for duration of study Patients must be able to understand and provide written informed consent Both men and women, and members of all races and ethnic groups are eligible for this trial. Subjects will be approximately representative of the demographics of the referral base for the participating institutions Patient must not have a known allergy to progesterone In females, no active vaginal bleeding Patients may not be enrolled on any other therapeutic trial for which they are receiving an anti-tumor therapy Exclusion Criteria: Patients with pacemakers, aneurysm clips, neurostimulators, cochlear implants, metal in ocular structures, history of being a steel worker, or other incompatible implants which makes MRI safety an issue are excluded Patients that have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy are excluded Patients with a history of severe hepatic dysfunction of disease are excluded Patients with a history of idiopathic jaundice, severe pruritus and pemphigoid gestationis during pregnancy are excluded Patients with a history of breast or genital tract cancer are excluded Patients with a history of any other invasive cancer (except non-melanoma skin cancer and excluding carcinoma in-situ), unless in complete remission and off all therapy for that disease for >= 3 years, are ineligible Patients with an active infection or serious intercurrent medical illness are ineligible Patients who received any other in anti-tumor agents (including investigational ones) must be off therapy for 4 weeks prior to initiating progesterone on study Patient receiving anti-coagulation therapy are excluded Patient with active or recent (within 6 months) thromboembolic disease are excluded Patient with current ongoing therapy with estrogen/progesterone (including hormonal contraceptives) are excluded. Would need to stop this form of birth control at least 7 days prior to initiation of therapy to be eligible

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (progesterone)<br>Patients receive progesterone SC QD for up to 24 weeks in the absence of disease progression or unacceptable toxicity. | Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Biological: Therapeutic Progesterone<br>* Given SC<br>* Other names: Utrogestan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Natural progesterone blood levels | This analysis will be performed to determine what plasma drug levels can be achieved in recurrent glioblastoma (GBM) patients with subcutaneous administration of natural progesterone and whether this is in line with what was previously determined in healthy subjects. | On day 1 (0, 30 minutes, 1, 2, 4, 6, 8 hours from drug injection) as well as at day 4 and day 8 prior to drug injections | 
| Incidence of adverse events | The safety of this approach will be confirmed by assessing toxicity potentially attributable to the daily progesterone treatment. Toxicity will be determined by Common Terminology Criteria for Adverse Events version 5.0 criteria. | Up to 2 years | 
| Overall response rate | Will be looking for the fraction of patients that are able to maintain at least stable disease. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | Patients on this study will be followed for PFS. In addition to the 24 weeks PFS, actuarial PFS curves will be assessed and compared to historical controls. | From the time of pre-treatment magnetic resonance imaging (MRI) to the time of either radiographic progression or death, whichever occurs first, assessed at 24 weeks | 
| Overall survival (OS) | Patients on this study will be followed for OS. In addition to the 24 weeks OS, actuarial OS curves will be assessed and compared to historical controls. | From the time of pre-treatment MRI to the time of death, assessed at 24 weeks |