C3651021: A PHASE 2b/3, RANDOMIZED, DOUBLE-BLIND STUDY TO INVESTIGATE THE EFFICACY, SAFETY, AND TOLERABILITY OF PONSEGROMAB (PF-06946860) COMPARED WITH PLACEBO BOTH WITH BACKGROUND FIRST-LINE CHEMOTHERAPY IN ADULT PARTICIPANTS WITH CACHEXIA AND METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA

This study evaluates ponsegromab compared with placebo, both administered with background first-line chemotherapy, in adult participants with cancer cachexia and metastatic pancreatic ductal adenocarcinoma. The primary objectives are to assess the effect of ponsegromab versus placebo on body weight and on appetite-related symptoms as measured by the FAACT-5IASS (Functional Assessment of Anorexia/Cachexia Therapy - 5 Item Anorexia/Cachexia Subscale). These endpoints are clinically relevant as cachexia-related weight loss and appetite impairment significantly impact patient outcomes and quality of life in advanced pancreatic cancer.

The secondary objectives include evaluation of ponsegromab compared with placebo on:

• Physical activity measured by wearable digital health technology (DHT) watch
• Overall survival
• Body composition
• Physical function and fatigue
• Progression-free survival (PFS)
• Objective response rate (ORR)
• Disease control rate (DCR)
• Duration of response (DOR)
• Tumor size
• ECOG performance status
• Chemotherapy administration parameters
• Temporal changes in body weight, appetite, physical activity, physical function, and fatigue
• Safety and tolerability profile

An open-label extension (OLE) component assesses the effect of ponsegromab on body weight and characterizes the safety and tolerability of repeated subcutaneous administrations.

This clinical trial enrolled a total of **693 participants** diagnosed with **cancer cachexia** associated with **metastatic pancreatic ductal adenocarcinoma (mPDAC)**. The study population included both **male and female subjects** aged **18 years or older**. Participants were selected based on specific clinical characteristics, including documented histologic or cytologic confirmation of active mPDAC with measurable metastatic disease according to RECIST v 1.1 criteria. Eligible individuals had completed one cycle of first-line systemic chemotherapy with nab-paclitaxel and gemcitabine or two cycles of FOLFIRINOX prior to enrollment. A key defining feature of the study population was the presence of cachexia according to Fearon criteria, characterized by either a **body mass index (BMI)** below 20 kg/m² with involuntary weight loss exceeding 2% within six months prior to screening, or involuntary weight loss greater than 5% over the past six months regardless of BMI. Participants were required to have an **ECOG performance status** of 1 or lower and a **life expectancy** of at least four months as assessed by the investigator. The trial population represented a **vulnerable population** due to the advanced nature of their disease and associated cachexia.

This is a Phase 2b/3, randomized, double-blind, placebo-controlled clinical trial designed to investigate the efficacy, safety, and tolerability of **ponsegromab** (PF-06946860) compared with **placebo**, both administered with background first-line **chemotherapy**, in adult participants with **cancer cachexia** and **metastatic pancreatic ductal adenocarcinoma**. The investigational medicinal product ponsegromab is a humanized IgG1 monoclonal antibody against growth/differentiation factor 15, administered as a solution for injection with a maximum daily dose of 400 mg and a maximum treatment period of 48 weeks. The placebo comparator is matched to ponsegromab. The trial aims to evaluate the effect of ponsegromab on body weight, with the primary endpoint being the percent change from baseline in body weight at Week 12. Additional primary endpoints include the change from baseline in appetite-related symptoms as measured by the FAACT-5IASS subscale scores at Week 12, and in the open-label extension phase, the percent change from baseline body weight.

Eligible participants must be aged 18 years or older with documented histologic or cytologic diagnosis of metastatic pancreatic ductal adenocarcinoma with measurable disease according to RECIST version 1.1. Participants must have completed one 28-day cycle of first-line systemic nab-paclitaxel and gemcitabine chemotherapy or two 14-day cycles of FOLFIRINOX chemotherapy prior to enrollment. Cachexia eligibility is defined by Fearon criteria, requiring either a **BMI** less than 20 kg/m² with involuntary weight loss greater than 2% within 6 months prior to screening, or involuntary weight loss greater than 5% over the past 6 months irrespective of BMI. Participants must have an **ECOG performance status** of 1 or less and a life expectancy of at least 4 months as assessed by the investigator.

The trial design includes a screening visit to assess eligibility criteria and baseline measurements. Following randomization, participants will receive either ponsegromab or placebo in combination with their ongoing first-line chemotherapy regimen. Study visits are scheduled at regular intervals to assess efficacy and safety parameters, including body weight measurements, physical activity monitoring using non-sedentary activity time and total vector magnitude, body composition analysis by CT scan at the third lumbar vertebra level, and tumor assessments by blinded independent central review according to RECIST 1.1. Secondary endpoints include **overall survival** defined as time from randomization to all-cause death, **progression-free survival**, **objective response rate**, **disease control rate**, and **duration of response**. Patient-reported outcomes are assessed using validated instruments including PROMIS Physical Function and Fatigue scales, and symptomatic adverse events are evaluated using the NCI PRO-CTCAE.

Safety assessments throughout the trial include monitoring of **treatment-emergent adverse events**, **serious adverse events**, adverse events leading to permanent discontinuation, clinical laboratory abnormalities, vital sign abnormalities, and **ECG** abnormalities. Specific attention is given to symptomatic adverse events including diarrhea, nausea, vomiting, decreased appetite, fatigue, and mouth sores. The trial also evaluates the occurrence of chemotherapy dosing changes, including dose reductions, dosing interruptions, and permanent treatment discontinuations due to adverse events. The study includes an open-label extension phase for participants who complete the randomized portion, with continued assessment of body weight changes and safety parameters.

The estimated recruitment start date is December 15, 2025, with an estimated study completion date of January 7, 2030. Participants may be withdrawn from the study due to adverse events requiring discontinuation, disease progression, withdrawal of consent, protocol violations, or investigator decision based on safety concerns. The maximum treatment duration with the investigational medicinal product is 48 weeks. Throughout the trial, tumor status is assessed at Week 12 and at subsequent time points using CT or MRI scans, with changes in ECOG performance status monitored at all collected time points. The trial methodology incorporates comprehensive safety monitoring, efficacy assessments, and quality of life measurements to evaluate the therapeutic potential of ponsegromab in this patient population with advanced pancreatic cancer and cachexia.

The experimental medication **Ponsegromab** (PF-06946860) is administered as a **solution for injection**. Ponsegromab is a **humanised IgG1 monoclonal antibody** directed against **growth/differentiation factor 15 (GDF15)**. The active substance is of biological/biotechnological origin classified as protein. The maximum daily dose is **400 mg**, with a maximum total dose of **400 mg**. The maximum treatment period is **48 weeks**. The product is manufactured by Pfizer Inc.

The comparator treatment consists of **placebo** matching Ponsegromab (PF-06946860). The placebo is administered to maintain the **double-blind** design of the study. Both the experimental medication and placebo are administered in conjunction with **background first-line chemotherapy** as part of the treatment regimen for participants with **cachexia** and **metastatic pancreatic ductal adenocarcinoma**.

Efficacy will be assessed through multiple parameters evaluating body weight, appetite-related symptoms, physical function, and tumor response. The primary efficacy endpoints include percent change from baseline in body weight at Week 12, change from baseline in FAACT-5IASS subscale scores at Week 12, and percent change from baseline body weight in the open-label extension. Secondary efficacy endpoints encompass change from baseline at Week 12 in physical activity as measured by time spent in non-sedentary activity and total vector magnitude, change from baseline in body weight (kg) at Week 12, and change from baseline in body composition as measured by CT scan at Week 12 and all other collected time points. CT or MRI based measures will include LSMI, skeletal muscle area and radiodensity at third lumbar vertebra (L3), intermuscular adipose area and radiodensity at L3, subcutaneous adipose area and radiodensity at L3, and visceral adipose area and radiodensity at L3.

Additional secondary endpoints include overall survival, defined as the time from randomization to occurrence of all-cause death, progression-free survival as determined by BICR assessment per RECIST 1.1, objective response rate as determined by BICR assessment per RECIST 1.1, disease control rate as determined by BICR assessment per RECIST 1.1, and duration of response as determined by BICR assessment per RECIST 1.1. Patient-reported outcomes will be evaluated through change from baseline at Week 12 in PROMIS-Physical Function (version 8c, 7-day) and PROMIS-Fatigue (version 7a). Changes from baseline at all collected time points will be assessed for body weight and percent change, FAACT Total and Sub-scale Scores including FAACT-5IASS, time spent in non-sedentary activity, total vector magnitude, PROMIS-Physical Function, and PROMIS-Fatigue. Tumor status will be determined by BICR assessment per RECIST 1.1 using CT scan or MRI at Week 12 and all other collected time points. Change from baseline at Week 12 and all other collected time points on ECOG performance status will also be evaluated.