Testosterone Replacement for Fatigue in Male Hypogonadic Advanced Cancer Patients

A Preliminary Trial of Testosterone Replacement for Fatigue in Male Hypogonadic Patients With Advanced Cancer.

The goal of this clinical research study is to learn if and how testosterone replacement therapy may affect fatigue in males with advanced cancer and low testosterone levels.

Background for Study:

Testosterone is the main sex hormone for males. Cancer, cancer treatments and cancer symptoms can cause its levels in the body to drop below normal. When testosterone is taken as a drug (called "testosterone replacement therapy"), this therapy is designed to return the testosterone levels to normal. This may help to control symptoms of low testosterone levels, which may include fatigue.

In addition to fatigue, low testosterone levels may also cause depression, loss of sexual desire, loss of appetite, and/or physical changes such as effects on strength, stamina (long-lasting strength and energy), energy level, and body composition. In this study, researchers also want to learn how testosterone therapy may affect these other symptoms that may occur. To measure these effects, questionnaires and other tests will be used.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the flip of a coin) to 1 of 2 groups. One group will receive testosterone, and the other group will receive a placebo. A placebo is a substance that looks like the study drug but has no active ingredients. There is an equal chance that you will be assigned to either group.

Neither you, the study doctor, nor the study staff will know whether you are receiving testosterone or placebo until Day 72. However, if needed for your safety, the study doctor and staff will be able to find out which one you are receiving.

You will receive testosterone or placebo by injection into your buttock muscle, about every 15 days until Day 72 (+/- 3 days). This is at baseline (+/- 3 days), Day 15 (+/- 3 days), Day 29 (+/- 3 days), Day 43 (+/- 3 days), and Day 57 (+/- 3 days).

As part of the routine blood tests performed at your study visits, your testosterone levels will be measured. If your testosterone level is too high, your testosterone/placebo dose will be lowered. If your testosterone level is too low, your testosterone/placebo dose will be raised.

Baseline Visit:

On Day 1, you will have a series of tests performed.

Your strength and stamina will be measured by hand-grip strength tests, a Get-Up-and-Go test and a 6-minute walk test.

• For the hand-grip strength tests, you will grip a device with your hand as hard as you can. You will repeat both of these tests 3 times for each hand.
• For the Get-Up-and-Go test, you will be timed to see how long it takes you to get up from sitting in a chair, walk 10 feet, turn around and walk back to the chair, and sit down.
• For the 6-minute walk test, you will be timed while you walk on a 100-foot loop. You will walk 50 feet and then turn and walk back to the beginning. You will do this at a walking speed that feels comfortable and for as many times as you can in 6 minutes.

A muscle on your upper arm will be measured. This will be the arm you do not normally use for writing.

You will be weighed on a scale that measures your body composition. Body composition includes measurements of your body fat, "lean" (non-fat) body weight, and how much water is in your body.

Blood (about 1-2 tablespoons) will be drawn for research on inflammation, other proteins and hormones. These tests are designed to help researchers learn if testosterone affects inflammation and/or fatigue, and if increased levels of certain hormones may help increase muscle and appetite.

You will be given a device called an Actiwatch, which is worn like a wristwatch. It will measure your physical activity. The research staff will show you how to use it. You should wear it through Day 29 of the study. You will return it at your Day 15 and Day 29 study visit.

Other Study Visits:

On Days 15, 29, 43, 57 and 72 (all +/- 3 days), the following tests and procedures will be performed:

• Blood (about 1 tablespoon) will be drawn for routine tests.
• You will complete questionnaires.
• Your strength and stamina, arm muscle, and body composition will be measured.
• A medical history and physical exam will be performed on Day 29 (+/-3 days) and Day 72 (+/3 days)

If your questionnaire responses show that you may be having emotional difficulties or depression, you will be provided with names of mental health providers in case you would like to receive mental health screening.

Length of Study:

You may remain on study until Day 72. You will be taken off study early if intolerable side effects occur, the cancer gets worse, or the fatigue gets worse.

Optional Open-Label Testosterone Dosing:

At your Day 72 visit, you will find out if you were receiving testosterone or placebo. Those participants who were receiving testosterone will be given the option to keep receiving testosterone (off-study). Those participants who were receiving the placebo will also be given the option to receive testosterone (off-study). This is called "Open-Label Testosterone Dosing."

If you choose to receive testosterone off-study after Day 72, you will receive testosterone by injection into your buttock muscle.

This is an investigational study. Testosterone replacement therapy is commercially available and FDA approved for use in men with HIV, for treating low testosterone levels and fatigue. (HIV is a virus that affects the immune system.) At this time, it is investigational to use testosterone replacement therapy to treat low testosterone levels and fatigue in patients with cancer.

Up to 126 patients will take part in this multicenter study. Up to 80 patients will be enrolled at M. D. Anderson Cancer Center.

Inclusion Criteria:

1. Male patients with any advanced cancer (metastatic or locally recurrent) who have a bioavailable testosterone (BT) of < 70 ng/dL.
2. Male patients who have fatigue present every day for the last two weeks and have an Edmonton Symptom Assessment System (ESAS) fatigue score during the last 24 hours of >/= to 4 on a 0 to 10 scale (in which 0 = no fatigue and 10 = worst possible fatigue).
3. Male patients who are willing to receive intramuscular injections every 2 weeks and are 18 years of age or older are eligible for this study.
4. Participants must be willing to have blood samples drawn at screening and/or baseline and every two weeks until the end of treatment.
5. Prostatic Specific Antigen (PSA) level must be lower than 4.0 ng/mL to be eligible for this study and Digital Rectal Exam (DRE) must be normal.
6. Eastern Cooperative Oncology Group (ECOG) PS </= 3 and participants must be able to stand up with or without assistance and to ambulate.
7. Hemoglobin (Hgb) >/= 9 g/dL. If the patient has not had blood drawn for a hemoglobin level in the past 28 days, one will be done to determine eligibility. Patients with a hemoglobin < 9 g/dL will be referred for treatment of their anemia.

Exclusion Criteria:

1. Patients who are determined incapable of completing questionnaires due to cognitive or physical deficits are ineligible for this study
2. Abnormal Digital Rectal Exam (DRE) at baseline or history of severe untreated benign prostatic hypertrophy (BPH) with International Prostatic Symptom Score (IPSS) >19.
3. Patients with a history of prostate cancer, a history of breast cancer or adenocarcinoma of unknown origin.
4. A history of untreated obstructive sleep apnea.
5. Uncontrolled severe heart failure (NYHA Class III or IV), uncontrolled cardiac arrhythmia or severe chronic obstructive pulmonary disease (COPD) requiring home oxygen.
6. Patients who have evidence of pre-existing hypopituitarism/hypogonadism including status post bilateral orchiectomy, for which replacement therapy is mandated, are ineligible for this study.
7. Patients exhibiting clinically diagnosed severe dehydration are ineligible.
8. Patients with a history of uncontrolled arrhythmia.
9. Patients who are currently receiving androgen therapy or dehydroepiandrosterone (DHEA)
10. Diabetics with a history of frequent episodes of hypoglycemia or uncontrolled diabetes mellitus (DM) defined as a fasting glucose over 200 mg/dL or HbA1c above 8%.
11. Uncontrolled thyroid disease
12. Hypercalcemia (corrected calcium > 10.5 g/dL); estimated glomerular filtration rate < 60 mg/min using the Modification of Diet in Renal Disease glomerular filtration rate (MDRD GFR); ALT > 3x the upper limit of normal (UNL)
13. Patients on warfarin, cyclosporine, dong quai, eucalyptus, dicumarol, germander, Jin bu huan, kava, pennyroyal, chaparral, comfrey, phenprocoumon are ineligible for this study.
14. Unstable symptoms could contribute to fatigue such as severe pain (score> 6 on ESAS) or severe depression (defined as a score of 15 or greater on the Depression Subscale of the Hospital Anxiety Depression Scale [HADS]). These symptoms should be resolved or stable for >/= 2 weeks at baseline for inclusion into study.
15. Patients with hematocrit (Hct) > upper normal limits (UNL) will be excluded due to possible polycythemia. If the patient has not had blood drawn for a hematocrit level in the past 28 days, one will be performed at baseline to determine eligibility.
16. Patients who have a known sensitivity to sesame seed products.