A Phase II Study of MAOA Inhibitor Plus Docetaxel in Patients Currently Receiving and Progressing on Docetaxel Therapy

Inclusion Criteria:

• Histological or cytological diagnosis of adenocarcinoma of the prostate
• Radiographic evidence of regional or distant metastases with suspected tumor in an area that is safe to biopsy
• Willingness to undergo a baseline tumor biopsy
• Evidence of castration resistant prostate cancer (CRPC) indicated by history of progression despite standard hormonal therapy (by PSA and/or imaging studies)
• Prior therapy with at least four cycles of docetaxel with at least one PSA measurement during docetaxel therapy that was lower than the pre-docetaxel baseline. Combination therapy that includes docetaxel and non-cytoxic agents (biologic agents) is allowable; prior treatment with weekly docetaxel is not allowable
• Evidence of early progression during (while on therapy or within 45 days of the last dose administered) docetaxel therapy defined as:
• Increasing serum PSA level: Three increasing measurements obtained after exposure to first-line docetaxel treatment are required; if the third PSA value is less than the second, an additional fourth test to confirm a rising PSA is acceptable
• AND/OR progressive measurable disease: at least a 20% increase in the sum of the longest diameters of measurable lesions over the smallest sum observed -or- the appearance of one or more new lesions as assessed by CT scan after exposure to first-line docetaxel treatment; measurable lesions include nodal lesions >= 20 mm in diameter or visceral/soft-tissue lesions >= 10 mm in diameter
• AND/OR bone Scan Progression: appearance of 2 or more new lesions on bone scan after exposure to first-line docetaxel treatment
• For patients who have been on anti-androgen therapy and had evidence of response to the addition of an anti-androgen (i.e. PSA reduction), patients must have discontinued anti-androgen therapy for at least six weeks (4 weeks for flutamide) without current evidence of an anti-androgen withdrawal response
• Evidence of MAOA expression (2 or higher) in metastasis biopsy specimen
• Serum testosterone levels < 50 ng/dL (unless surgically castrate); patients must continue androgen deprivation with an LHRH agonist if they have not undergone orchiectomy
• ECOG performance status =< 2
• At least 15 days has passed since receiving the last dose of docetaxel at the time of initiation of study drug
• Has recovered from all therapy-related toxicity to =< grade 2 (except alopecia, anemia and any signs or symptoms of androgen deprivation therapy)
• Absolute neutrophil count >= 1500/uL
• Platelets >= 100,000
• Bilirubin =< 1.5 times ULN (if total bilirubin elevated, but direct is WNL, patient is eligible)
• creatinine =< 1.5 times upper limit of normal (ULN)
• ALT =< 2.5 times ULN
• PSA > 2 ng/mL
• Life expectancy > 3 months
• Signed informed consent
• For patients who meet all of the above criteria, but have been off docetaxel therapy for more than 6 weeks, current evidence of progression is also required

Exclusion Criteria:

• Received any other cytotoxic chemotherapy as a second-line treatment after first-line docetaxel-based therapy
• Significant peripheral neuropathy defined as grade 2 or higher
• A second active malignancy except adequately treated non-melanoma skin cancer or other non-invasive or in situ neoplasm
• Significant active concurrent medical illness or infection precluding protocol treatment or survival
• Current uncontrolled hyperthyroidism
• Pheochromocytoma
• Carcinoid Syndrome
• Known or suspected brain metastases
• Treatment with radiotherapy within the past 4 weeks or radiopharmaceutical therapy (strontium, samarium) within the past 8 weeks
• Concurrent therapy with a Selective Serotonin Reuptake Inhibitor (SSRI), tricyclic antidepressant, or Monoamine Oxidase Inhibitor (MAOi); clinical judgment should be used in a decision to discontinue antidepressants; a minimum of a 1 week washout period is required for any tricyclic or related antidepressant, or any SSRI (2 weeks for paroxetine or sertraline, 5 weeks for fluoxetine); minimum 2 week washout for any MAOi
• Concurrent therapy: Excluded Concomitant medications: Sympathomimetic drugs or related compounds: Amphetamine, Dextroamphetamine, Benzphetamine, Dexmethylphenidate, Methamphetamine, phentermine, cocaine, methylphenidate, dopamine, epinephrine, norepinephrine, methyldopa, L-dopa (levodopa), L-tryptophan, L-tyrosine, Phenylalanine, Ephedrine, Isometheptene, Levonordefrin, Midodrine, meperidine (e.g., Demerol); other Monoamine oxidase (MAO) inhibitors: isocarboxazid (e.g., Marplan), procarbazine (e.g., Matulane), selegiline (e.g., Eldepryl), tranylcypromine (e.g., Parnate), pargyline hydrochloride, pargyline hydrochloride and methylclothiazide, furazolidone, rasagiline, buspirone HCL; Serotoninergic Drugs: fluvoxamine (e.g., Luvox), fluoxetine (e.g., Prozac), paroxetine (e.g., Paxil), sertraline (e.g., Zoloft), dexfenfluramine, citoprolam, venlafaxine, desvenlafaxine, duloxetine, escitalopram, milnacipran, Atomoxetine
• Barbiturates, such as: Amobarbital, Butalbital, Pentobarbital, Phenobarbital, Secobarbital; Cough, Cold and Allergy products, such as: Dextromethorphan, Naphazoline, Oxymetazoline, Phenylephrine, Propylhexedrine, Pseudoephedrine; Tryptophan, Disulfiram, Entacapone, Reserpine, Sibutramine, Tolcapone, Bupropion HCL, guanethidine, serotonin receptor agonists (e.g. sumatriptan); Dibenzazepine Derivative Drugs: , nortriptyline hydrochloride, amitriptyline hydrochloride, perphenazine and amitriptyline hydrochloride, clomipramine hydrochloride, desipramine hydrochloride, imipramine hydrochloride, doxepin, carbamazepine, cyclobenzaprine HCl, amoxapine, maprotiline HCl, trimipramine maleate, protriptyline HCl, mirtazapine
• Other chemotherapeutic agents or biological response modifiers will be prohibited for the duration of the study
• All herbal supplements will be prohibited
• The following foods and beverages must be avoided: Meat and Fish: Pickled herring, Liver, Dry sausage (including Genoa salami, hard salami, pepperoni, and Lebanon bologna); Vegetables: Broad bean pods (fava bean pods), Sauerkraut; Dairy Products: Cheese (particularly aged cheeses, cottage cheese and cream cheese are allowed), Yogurt; Beverages: Beer and wine, Alcohol-free and reduced-alcohol beer and wine products; Miscellaneous: Yeast extract (including brewer's yeast in large quantities), Meat extract, Excessive amounts of chocolate and caffeine
• Systemic steroids other than as premedication will not be allowed on the study
• While concurrent use of narcotic analgesics is not prohibited, phenelzine is known to interact with a variety of narcotic agents resulting in potential for greater CNS depression, respiratory depression, and hypotension. Caution should be exercised in patients who are regularly taking narcotic analgesics, particularly higher doses. The doses of narcotic analgesics may need to be reduced, patients may need to be monitored closely for drug interactions, and the risks and benefits of participation in the study should be considered. Clinical judgment should be exercised to manage this potential drug interaction.