Olanzapine for the Management of Cancer Associated Appetite Loss in Patients With Advanced and Incurable Solid Tumors

Study Overview
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Brief Summary
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This phase II trial tests how well olanzapine may work in managing cancer cachexia in patients experiencing advanced solid tumor cancer-associated appetite loss while receiving non-curative cancer therapy. Loss of appetite (anorexia) in the setting of cancer is a key feature of cachexia, a syndrome associated with loss of weight and muscle as well as weakness and fatigue. Olanzapine is a type of drug that targets key neurotransmitters (a type of molecule used by the brain to transmit messages to the rest of the body) that may stimulate appetite, restore caloric intake, minimize weight loss, and improve quality of life.

Detailed Description
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PRIMARY OBJECTIVE: I. To assess the effect of olanzapine versus placebo for decreasing cancer-associated anorexia at 2 weeks for patients with advanced cancer receiving systemic therapy. SECONDARY OBJECTIVE: I. To evaluate the longitudinal impact of olanzapine versus placebo over 6 weeks on food intake, anthropometric measures, physical function, patient-reported symptoms, quality of life, toxicity, and healthcare utilization. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive 5mg of olanzapine orally (PO) nightly for six weeks on study. Patients may also undergo an optional computed tomography (CT) scan and blood sample collection on the study. ARM II: Patients receive placebo PO nightly for six weeks and then receive 5mg of olanzapine PO nightly for 6 weeks (i.e., wait-list control). Patients may also undergo an optional CT scan and collection of blood samples on the study.

Official Title
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ACTO: A Phase II, Randomized, Placebo-Controlled Study Evaluating Olanzapine in the Management of Cancer Cachexia

Conditions
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Advanced Malignant Solid Neoplasm

Intervention / Treatment
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* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Drug: Olanzapine
* Drug: Placebo Administration
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness to provide written informed consent. Individuals >= 18 years of age of all races, ethnicities, sexual orientations, gender identities, and abilities may be screened for enrollment without bias Histologically confirmed advanced and incurable solid tumor cancer diagnosis within 12 weeks of screening. Cancer diagnoses will include those for which standard curative measures do not exist or are no longer effective Planned or ongoing standard of care (SOC) systemic antineoplastic therapy without curative intent (concurrent to this study) Able to ambulate independently with or without assistive devices (e.g., cane, walker). In the case of brain metastases, the individual must be asymptomatic or previously treated with a full cycle of therapy such that recovery from any acute effects of radiation therapy or surgery has occurred before the screening. Such individuals must have discontinued corticosteroid treatment and be neurologically stable for at least 4 weeks before screening Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Able and willing to discontinue the use of any drug or over-the-counter (OTC) product that may interact with the study drug (within a period sufficient for wash-out per the investigator's discretion) and thereafter while on the study Willingness to comply with restrictions on chest/breastfeeding Individuals capable of childbearing and contributing viable sperm must be willing to comply with contraception requirements and not donate ova or sperm while on the study and for 1 month after that A negative pregnancy test at baseline must be obtained for individuals capable of childbearing Exclusion Criteria: Plan for, or history of (within 30 days of registration), the use of an antipsychotic drug, including, but not limited to risperidone, quetiapine, clozapine, phenothiazine, or butyrophenone. This limitation does not include prochlorperazine and other phenothiazines as antiemetic therapy. The use of antipsychotics concurrent with protocol therapy will not be allowed Previous or current use of megestrol acetate, cannabinoids (including, but not limited to dronabinol, medical cannabis, over the counter [OTC] cannabinoids products), and/or corticosteroids (defined as >= 5mg of prednisone or equivalent per day, except for standard chemotherapy-induced nausea and vomiting [CINV] prophylaxis) during the proceeding >=14 days Known history of poorly controlled diabetes, defined as fasting morning blood sugars > 300 mg/dL or recent hemoglobin A1c >= 8 Inadequate organ function, which may include, but is not limited to, the following laboratory results within 28 days before signing consent: Total bilirubin > upper limit of normal (ULN), aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SPGT]) > 2.5 ULN (unless the participant has documented Gilbert's syndrome, hepatocellular carcinoma, or hepatic metastases) Serum creatinine > 2.0 mg/dL or calculated glomerular filtration rate (GFR) >= 30 mL/minute/1.73 m^2 as calculated by the modification of diet in renal disease (MDRD) equation NOTE: Investigator discretion will determine continued eligibility after randomization occurs in the event the liver function test results are greater than (>) the proposed upper limit of normal Tube feeding or parenteral nutrition at the time of screening Any condition that may negatively impact oral absorption of the study drug (including, but not limited to dysphagia, mucositis, gastrectomy, colitis, bowel obstruction, high output ileostomy) or any plan to undergo an intervention that will render such a condition Recurrent ascites unresponsive to medical interventions and requires therapeutic paracentesis Uncontrolled symptoms (including, but not limited to, pain and nausea) at randomization make the individual unsuitable for the study in the judgment of the principal investigator (PI). If uncontrolled symptoms can be effectively palliated for >= 1 week prior, enrollment may be considered at the discretion of the PI Uncontrolled infection, including coronavirus disease 2019 (COVID-19), at time of randomization. Individuals with the uncontrolled infection will not be eligible as the symptomology of infection may obscure the outcomes of this study Other medical or psychiatric condition, including recent (within 1 year) or active suicidal ideation/behavior or laboratory abnormality, may increase the risk of study participation or, in the investigator's judgment, makes the participant inappropriate for the study

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (olanzapine, optional biospecimen collection)<br>Patients receive olanzapine PO for six weeks on study. Patients may also undergo an optional CT scan and blood sample collection on the study. | Procedure: Biospecimen Collection<br>* Undergo blood specimen collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo a CT scan<br>* Other names: tomography;Drug: Olanzapine<br>* Given PO<br>* Other names: Zyprexa Zydis;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Arm II (placebo, olanzapine, optional biospecimen collection)<br>Patients receive placebo PO for six weeks and then receive olanzapine PO for 6 weeks. Patients also undergo an optional CT scan and collection of blood samples on study. | Procedure: Biospecimen Collection<br>* Undergo blood specimen collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo a CT scan<br>* Other names: tomography;Drug: Olanzapine<br>* Given PO<br>* Other names: Zyprexa Zydis;Drug: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in self-reported severity of anorexia | Measured using the 5-item Functional Assessment of Anorexia-Cachexia Therapy (FAACT) assessment. Numerical scale goes from 0-20, with higher scores indicate less anorexia/cachexia. | Baseline to 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food intake | Measured using Ingesta score. The Ingesta food intake scoring tool is and 11-point numerical scale over 24 hours going 0 (eating nothing at all) to 10 (eating as usual). | At to 2, 4, and 6 weeks from baseline | 
| Anthropometric measures: weight (kg) | Weight will be captured using the same properly calibrated scale at the same time of day without shoes. | At 2, 4, and 6 weeks from baseline | 
| Anthropometric measures: body mass index (kg/m^2) | Weight will be captured using the same properly calibrated scale at the same time of day without shoes. | At 2, 4, and 6 weeks from baseline | 
| Physical function: performance status | Measured using Eastern Cooperative Oncology Group (ECOG) performance status. ECOG is a clinician's assessment of physical function rated on numerical scale going from 0 (fully active) to 5 (dead). | At 2, 4, and 6 weeks from baseline | 
| Physical function: short physical battery assessment | Measured using a Short Physical Performance Battery assessment (SPPB), a physical function assessment consisting of 3 timed measures and scored 0 to 12. Scores of 2 or lower indicate mobility disability and 10 or higher indicate no mobility disability / robustness. | At 2, 4, and 6 weeks from baseline | 
| Physical function: handgrip strength | Handgrip strength (HGS) will be measured in kilograms (kg) by handgrip dynamometry to assess arm strength. | At 2, 4, and 6 weeks from baseline | 
| Patient-reported symptoms and quality of life: FACT-G | Measured using Functional Assessment of Cancer Therapy - General (FACT-G) Scores go from 0-108, higher scores indicate better QOL, including physical (0-28), social (0-28), emotional (0-24), and functional (0-28). | At 2, 4, and 6 weeks from baseline | 
| Patient-reported symptoms and quality of life: FAACT | Measured using the longitudinal changes on the Functional Assessment of Anorexia-Cachexia Therapy (FAACT). Scale goes from 0-20, with higher scores indicate less anorexia/cachexia | At 2, 4, and 6 weeks from baseline | 
| Patient-reported symptoms and quality of life: PRO-CTCAE | Measured using Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Scores go from 0-4 for each item, higher scores indicate more severity, specifically none (0), mild (1), moderate (2), severe (3), and very severe (4). | At 2, 4, and 6 weeks from baseline | 
| Patient-reported symptoms and quality of life: PGI-C | Measured using Patient Global Impression of Change (PGI-C) assessments. This measure patient belief about the overall treatment efficacy. Scores go from 0-14, higher scores indicate greater global improvement. | At 2, 4, and 6 weeks from baseline | 
| Incidence of adverse events | Measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. The NCI CTCAE is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. A grading (severity) scale is provided for each AE term. Grades go from 1 (mild) to 5 (death). | At 2, 4, and 6 weeks from baseline | 
| Healthcare utilization | Measured using emergency department visits and unplanned hospitalizations. | At 2, 4, and 6 weeks from baseline |