Summary

This phase III trial compares the effects of olanzapine versus megestrol acetate in treating loss of appetite in patients with cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Olanzapine is studied in the treatment of nausea and vomiting caused by some cancer treatments and may stimulate and increase appetite. Megestrol acetate works by stimulating patients appetites in order to treat or prevent weight loss. This study is looking at the effect of olanzapine on appetite and weight loss in patients with advanced cancer and determining whether it is better or worse than megestrol acetate.

Objectives

PRIMARY OBJECTIVE:
I. To determine whether olanzapine leads to greater appetite improvement from baseline in cancer patients suffering from anorexia compared to megestrol acetate using the 0-10 numerical rating scale (NRS).

SECONDARY OBJECTIVES:
I. To determine whether olanzapine leads to a greater proportion of patients who report a 5% or greater weight gain from baseline compared to megestrol acetate.
II. To compare change in cachexia/anorexia symptoms with olanzapine compared to megestrol acetate using the Functional Assessment of Anorexia/Cachexia Treatment (FAACT)-Anorexia/Cachexia Subscale (A/CS) instrument.

EXPLORATORY OBJECTIVES:
I. To describe the trajectory of appetite scores from baseline to end of treatment by arm using the NRS.
II. To describe the trajectory of weight from baseline to end of treatment by arm.
III. To explore the difference in trajectory of nausea, vomiting, fatigue, pain, quality of sleep, anxiety/stress, and sense of taste and smell from baseline to end of treatment between olanzapine and to megestrol acetate.
IV. To explore whether olanzapine will decrease the use of other antiemetic drugs compared to megestrol acetate.
V. To describe the adverse event profiles of olanzapine versus megestrol acetate.
VI. To report weekly appetite change by treatment and race/ethnicity.

OUTLINE: Patient are randomized to 1 of 2 arms.

ARM I: Patients receive olanzapine orally (PO) once daily (QD) for up to 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive megestrol acetate PO QD for up to 4 weeks in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at screening and may undergo additional blood sample collection on study.

At the end of the study intervention, patients are followed within 30 days.

Eligibility

1. Clinicians should be aware of drug interactions between the agents used in this study and drugs that can prolong the QT interval, that can induce or inhibit CYP1A2, or that can function as an anticholinergic. Clinicians should use their clinical judgment to decide whether the doses and duration of such agents is such that they can be used concurrently with the medications prescribed in this study
2. Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
3. Diagnosis of advanced cancer
4. Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or physician-estimated caloric intake of less than 20 calories/kilogram of body weight per day
5. The patient must perceive loss of appetite and/or weight as a problem; and have an appetite score of 4 or worse on the “Please rate your appetite….” question that requires a patient response on a 0-10 numeric rating scale
6. Not receiving ongoing tube feedings or parenteral nutrition at the time of registration
7. Not currently using systemic adrenal steroids (with the exception of short-term dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
8. No use of androgens, progesterone analogs, or other appetite stimulants within the past month
9. Patient should not have poorly controlled hypertension, defined as multiple blood pressure readings with systolic levels above 160 and diastolic levels above 100 or congestive heart failure at registration
10. Patient should not have an obstruction of the alimentary canal, malabsorption, or intractable vomiting (defined as vomiting more than 3 times per day over the preceding week)
11. Not currently using olanzapine for another medical condition or had previously used olanzapine for chronic nausea or for any pre-existing psychotic disorder
12. Patients with impaired decision-making capacity from any etiology (such as with a diagnosis of dementia or memory loss) are not eligible for this study
13. No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate cancer (this exclusion criterion is intended to circumvent any confounding antineoplastic effects of megestrol acetate)
14. Patient should not have had a previous blood clot at any time in the past
15. No history of poorly controlled diabetes
16. No symptomatic leptomeningeal disease or known brain metastases as these patients may have difficulty taking oral medications
17. No history of hypersensitivity to olanzapine or megestrol acetate
18. No coronavirus disease 2019 (COVID-19) infection in the past that, in the opinion of the treating physician, had left patients with compromised taste, which has not resolved at the time of registration
19. Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 14 days prior to registration is required
20. Age >= 18 years
21. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
22. Estimated life expectancy of 3 months or longer
23. Creatinine =< 2.0 mg/dL
24. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
25. Glucose =< 140 mg/dL
26. Granulocytes >= 1000/mm^3
27. No treatment with another antipsychotic agent, such as risperidone, quetiapine, clozapine, butyrophenone within 30 days of enrollment
28. In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking patients should have access to Spanish speaking staff on site or through the use of a translation service to be able to conduct the informed consent discussion in Spanish, and to conduct the weekly phone calls