Methylphenidate and Physical Activity to Reduce Cancer Related Fatigue Due to Anti PD1 Immunotherapy

Study Overview
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Brief Summary
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This phase III trial studies how well methylphenidate and physical activity works in reducing cancer-related fatigue in patients who are receiving anti-PD1 immunotherapy for cancer that has spread to other places in the body. Central nervous systems stimulants, such as methylphenidate, may help to improve cognitive function. Physical activity uses techniques, such as aerobic and resistance exercises, which may help to improve quality of life. Giving methylphenidate and physical activity may help in reducing cancer-related fatigue in patients with metastatic cancer who receive anti-PD1 immunotherapy.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the effects of methylphenidate plus physical activity (MP) compared to placebo plus physical activity (PL) in reducing cancer-related fatigue (CRF) in patients with metastatic cancer on anti-PD1 immunotherapy, as measured by changes in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale scores after 2 weeks of intervention. SECONDARY OBJECTIVES: I. To explore the effect of MP on anxiety (Hospital Anxiety and Depression Scale [HADS]), depressed mood (HADS), cancer symptoms (Edmonton Symptom Assessment Scale (ESAS), physical activity (mean day time activity as measured by actigraphy), and serum levels of inflammatory cytokines (IL-1beta, IL-1 RA, IL-6, TNF-alpha, IL-8, IL-10, and MCP1), before and after treatment. EXPLORATORY OBJECTIVES: I. To determine the frequency and factors associated with CRF as assessed by FACIT-F, Patient-Reported Outcomes Measurement Information System Fatigue (PROMIS-F), Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), actigraphy, Edmonton Symptom Assessment System (ESAS), and serum levels of inflammatory cytokines (IL-1beta, IL-1 RA, IL-6, TNF-alpha, IL-10, IL-8, MCP-1), before and during 4 initial doses of Immunotherapy. II. To explore the effects of MP on percentage (%) of patients with dose reduction and/or discontinuation anti-PD1 immunotherapy due to CRF. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive methylphenidate orally (PO) twice daily (BID) for up to 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete physical activity consisting of walking and resistance exercise over 25-40 minutes once daily (QD) 4 days a week. After 2 weeks, patients may continue methylphenidate at the discretion of the treating physician for up to 12 weeks in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive a matched placebo PO BID and complete physical activity as in Arm I.

Official Title
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A Study of Cancer Related Fatigue in Patients With Metastatic Cancer Receiving Anti-PD1 Immunotherapy

Conditions
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Advanced Malignant Neoplasm, Metastatic Malignant Neoplasm, Recurrent Malignant Neoplasm

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Methylphenidate
* Other: Physical Activity
* Other: Placebo
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part 1: have a diagnosis of metastatic or recurrent cancer and previously received anti PD1 immunotherapy provided that they received therapy up to 1 month prior to enrollment Part 1: be willing to engage in follow-up telephone calls with a research staff Part 1: have telephone access so they can be contacted by the research staff Part 1: hemoglobin level of >= 8 g/dL within 2 weeks of enrollment * Packed red blood cell (PRBC) transfusions will be allowed to patients with hemoglobin < 8 g/dl Part 1: be able to understand the description of the study and give written informed consent Part 1: able to read, write and speak English Part 2: have a diagnosis of metastatic or recurrent cancer and previously received anti PD1 immunotherapy provided that they received therapy up to 1 month prior to enrollment Part 2: be willing to engage in follow-up telephone calls with a research staff Part 2: have telephone access so they can be contacted by the research staff Part 2: have a hemoglobin level of >=8 g/dL within 2 weeks of enrollment * PRBC transfusions will be allowed to patients with hemoglobin < 8 g/dl Part 2: be able to understand the description of the study and give written or verbal informed consent Part 2: able to read, write and speak English Part 2: presence of fatigue as defined FACIT-F subscale of =< 34 on a 0 to 52 scale (in which 52 = no fatigue and 0 = worst possible fatigue) Part 2: not currently taking methylphenidate, or have taken it within the previous 10 days Part 2: able to complete the baseline assessment forms Part 2: able to understand the recommendations for participation in the study Part 2: can be enrolled directly to part 2 independent of part 1 if on immunotherapy and having a FACIT-F fatigue =< 34, and able to complete baseline assessment and bloodwork as detailed in Part 1 at baseline and day 14 +/-3 days. Treating Oncologist should agree for participation in the intervention trial Exclusion Criteria: Part 1: patients will be excluded if (1) have clinical evidence of cognitive failure as evidenced by Memorial Delirium Assessment Scale score of >= 13 at baseline completed in person, by phone, or via video-conference Part 2: Patients will be excluded if (1) have clinical evidence of cognitive failure as evidenced by Memorial Delirium Assessment Scale score of >= 13 at baseline completed in person, by phone, or via video-conference Part 2: have a major contraindication to MP (e.g., allergy/hypersensitivity to study medications or their constituents), or conditions making adherence difficult as determined by the attending physician Part 2: on monoamine oxidase inhibitors, tricyclic antidepressants, or clonidine Part 2: history of glaucoma Part 2: history of have severe cardiac disease (New York Heart Association functional class III or IV) Part 2: tachycardia and/or uncontrolled hypertension Part 2: currently receiving anticoagulants, anticonvulsants (phenobarbital, diphenylhydantoin, primidone), phenylbutazone, and/or tricyclic drugs (imipramine, clomipramine, or desipramine) Part 2: patients with Cut Down, Annoyed, Guilty and Eye Opener-Adapted to Include Drugs (CAGE-AID) >= 2

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM I (methylphenidate, physical activity)<br>Patients receive methylphenidate PO BID for up to 2 weeks in the absence of disease progression or unacceptable toxicity. Patients also complete physical activity consisting of walking and resistance exercise over 25-40 minutes QD 4 days a week. After 2 weeks, patients may continue methylphenidate at the discretion of the treating physician for up to 12 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Methylphenidate<br>* Given PO<br>* Other names: Daytrana;Other: Physical Activity<br>* Participate in physical activity<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: ARM II (placebo, physical activity)<br>Patients receive a matched placebo PO BID and complete physical activity as in Arm I. Treatment continues for up to 2 weeks in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Physical Activity<br>* Participate in physical activity<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;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 |
| --- | --- | --- |
| Assessment of the effects of methylphenidate (MP) plus physical activity in reducing cancer-related fatigue (CRF) | Effects of MP to be compared to placebo plus physical activity results. To be as measured by changes in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) sub-scale scores. A t test will be used to evaluate the difference between groups unless the data appear to be non-normally distributed, in which case a Wilcoxon rank-sum test will be used to evaluate the difference between groups. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of MP effects on physical activity | To be measured by mean day time activity (actigraphy). To be evaluated using descriptive statistical analyses. A t test will be used to evaluate the difference between groups unless the data appear to be non-normally distributed, in which case a Wilcoxon rank-sum test will be used to evaluate the difference between groups. Will summarize percentage (%) of patients with stable CRF scores, % patients who had dose change and/ or discontinuation of anti-PD1 immunotherapy due to CRF. | Up to 12 weeks | 
| Assessment of MP effects on anxiety, depressed mood, and cancer symptoms by questionnaires | To be assessed using statistical methods described in primary outcomes and using outcome variables including Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) for fatigue dimensions | Up to 5 minutes during visit | 
| Assessment of MP effects on anxiety, depressed mood, and cancer symptoms by questionnaires | To be assessed using statistical methods described in primary outcomes and using outcome variables including Patient-Reported Outcomes Measurement Information System Fatigue (PROMIS) for fatigue dimensions | Up to 5 minutes during visit | 
| Assessment of MP effects on anxiety, depressed mood, and cancer symptoms by questionnaires | To be assessed using statistical methods described in primary outcomes and using outcome variables including Hospital Anxiety and Depression Scale (HADS) for anxiety/depression | Up to 5 minutes during visit | 
| Assessment of MP effects on anxiety, depressed mood, and cancer symptoms by questionnaires | To be assessed using statistical methods described in primary outcomes and using outcome variables including Functional Assessment of Cancer Therapy-General (FACT-G) for Quality of Life. | Up to 5 minutes during visit | 
| Assessment of MP effects on anxiety, depressed mood, and cancer symptoms by questionnaires | To be assessed using statistical methods described in primary outcomes and using outcome variables including Edmonton Symptom Assessment System (ESAS), (0-10 scale for sleep disturbance, fatigue, and drowsiness). | Up to 5 minutes during visit |