This phase III trial studies how well bupropion works in reducing cancer related fatigue in cancer survivors. Cancer and its treatment can cause fatigue. Bupropion is a drug that is used to treat depression, as well as to help people quit smoking. It belongs to the family of drugs called antidepressants and works by increasing certain types of activity in the brain. Bupropion may reduce cancer-related fatigue by causing changes in inflammation and stress hormones.

PRIMARY OBJECTIVE:

I. To determine the efficacy of bupropion hydrochloride controlled-release (bupropion) versus placebo in reducing fatigue in a double-blinded, placebo-controlled, randomized clinical trial of cancer survivors with fatigue.

SECONDARY OBJECTIVES:

I. To assess the efficacy of bupropion versus placebo on depression and quality of life in cancer survivors with fatigue.

II. To assess the tolerability of bupropion in cancer survivors with fatigue.

EXPLORATORY OBJECTIVES:

I. To assess the efficacy of bupropion versus placebo on symptomatology and cognition in cancer survivors with fatigue.

II. To explore the effects of bupropion on putative mechanisms of cancer-related fatigue.

III. To explore associations of CYP2B6 genotype with bupropion metabolism and changes in fatigue.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive bupropion hydrochloride controlled-release orally (PO) once daily (QD) for up to 13 weeks in the absence of unacceptable toxicity. Patients also undergo blood sample collection throughout study.

ARM II: Patients receive placebo PO QD for up to 13 weeks in the absence of unacceptable toxicity. Patients also undergo blood sample collection throughout study.

Inclusion Criteria:

• Be at least 18 years of age
• Be diagnosed with cancer
• Have stable disease or no evidence of disease
• Report WORST level of fatigue in the past week as moderate to severe (i.e., a score >= 4 on a 0-10 scale, screening measures, question 1)
• Have completed surgery, radiation, and/or systemic intravenous anticancer therapy (e.g., chemotherapy, targeted therapy, immunotherapy) 2 or more months prior to enrollment. Participants currently receiving oral maintenance, targeted, or hormonal therapy are eligible. Participants receiving intravenous supportive therapy (e.g., bisphosphonates) are eligible
• Able to read and speak English
• Currently not pregnant or breastfeeding. Women of child-bearing potential must agree to use adequate contraception, i.e, abstinence, IUD (intrauterine device), hormonal contraceptive (birth control pills) or barrier method (condoms) prior to study entry and for the duration of study participation
• Be capable of providing written informed consent

Exclusion Criteria:

• Be receiving intravenous anti-cancer therapy (e.g., intravenous immune checkpoint inhibitor therapy, targeted therapy)
• Be currently taking any medications that contain bupropion (e.g., Wellbutrin, Forfivo, Aplenzin, or Zyban)
• Be taking an monoamine oxidase inhibitor (MAOI), linezolid, or methylene blue within two weeks prior to enrollment
• Be taking any anti-psychotic medications within a week prior to enrollment
• Have a history of renal impairment (i.e., glomerular filtration rate < 45)
• Have a history of cirrhosis (i.e., Child-Pugh score >= 5)
• Have a history of seizures
• Have a history of bulimia or anorexia nervosa
• Report a history of sensitivity to bupropion
• Report an allergy to lactose
• Have psychiatric or neurological disorder(s) that would interfere with study participation per physician or physician's designee