Study to Assess the Safety and Tolerability of Repeated Doses of an Investigational New Drug in Patients With Cancer and Cachexia.

This 12-week open-label study will explore how PF-06946860 is tolerated, the effects of the study drug, the best dose for treatment and how participants with non-small cell lung, pancreatic or colorectal cancer and cachexia feel after receiving repeated subcutaneous dosing. During the 12-week treatment period, study drug will be administered subcutaneously every 3 weeks for a total of 5 doses. There is a 12-week follow-up period following the last dose of study drug. Additional assessments include:

• body weight measurements
• blood pressure and heart rate measurements
• Lumbar Skeletal Muscle Index (LSMI) by CT scan
• Blood samples:

• to evaluate safety,
• to measure the amount of the study drug in the blood,
• to evaluate if the study drug causes an immune response,
• to examine the effects of the study drug on levels of a specific cytokine,
• and for exploratory samples for bio banking.
• Measure the impact of the study drug on appetite, nausea, vomiting, fatigue, physical function, and health-related quality of life with questionnaires.
• Measure the impact of study drug on physical activity using wearable digital sensors.
• To evaluate the effect of study drug on ability to complete anti-tumor treatment and survival in participants with cancer and cachexia.
• To evaluate tumor size.

Inclusion criteria

• Documented histologic or cytologic diagnosis of advanced metastatic NSCLC, advanced/unresectable pancreatic cancer, or metastatic colorectal cancer.
• Cachexia, defined by BMI <20 kg/m2 with involuntary weight loss of >2% within 6 months prior to screening or Involuntary weight loss of >5% within 6 months prior to screening irrespective of BMI or If medical record documentation is unavailable, patient's report will suffice to estimate involuntary body weight loss.;
• Will receive the following for non-small cell lung cancer:

• a platinum + pemetrexed ± pembrolizumab or
• a platinum + nab paclitaxel or paclitaxel ± pembrolizumab or
• pembrolizumab alone
• Will receive the following for pancreatic cancer:

• FOLFIRINOX or
• Nab-Paclitaxel + Gemcitabine
• Gemcitabine
• Will receive the following for colorectal cancer:

• FOLFOX +/- Biologic (Bevacizumab or Cetuximab/Panitumumab) or
• FOLFIRI +/- Biologic (Bevacizumab or Cetuximab/Panitumumab) or
• FOLFOXIRI +/- Biologic (Bevacizumab or Cetuximab/Panitumumab) or
• Pembrolizumab for MSI-H • Will be entering the study at the first or second cycle of their current course of anti-cancer treatment/ therapy.
• Adequate renal and liver function.
• Signed informed consent.

Exclusion criteria

• All other forms of cancers not specified above unless currently considered cured (>5 years without evidence of recurrence).
• Planned radiation therapy as part of the primary anti-tumor therapy regimen. However, localized radiation therapy for symptomatic relief is permitted
• Cachexia caused by other reasons: Severe COPD requiring use of home O2, heart failure or AIDS.
• known symptomatic brain metastases requiring steroids.
• Active hepatitis B or C virus.
• Confirmed positive HIV test.
• Current active reversible causes of decreased food intake.
• Receiving tube feedings or parenteral nutrition at Screening.
• Elevated blood pressure that cannot be controlled by medications.
• Women who are pregnant or breast-feeding