A Study to Learn About the Medicine Ponsegromab in Adults With Cancer of the Pancreas Which Has Spread and Caused Significant Body Weight Loss and Fatigue

A Phase 2b/3, randomized, double-blind, multicenter, multinational study to investigate the efficacy, safety and tolerability of systemic chemotherapy plus ponsegromab versus systemic chemotherapy plus placebo for the first-line treatment in adult participants with cachexia and mPDAC. The first-line chemotherapies will either be nab-paclitaxel plus gemcitabine or FOLFIRINOX (or mFOLFIRINOX). The double-blind period is followed by an optional open-label extension period.

Initial enrollment will be in Phase 2b. If all eligibility criteria are met, participants will be randomized in a 1:1:1 allocation to study intervention (one of the two doses of ponsegromab, or placebo) plus first-line systemic chemotherapy. Participants must have completed their first-line pre-randomization systemic chemotherapy (1 x 28-day cycle of nab-paclitaxel and gemcitabine or 2 x 14-days cycles of FOLFIRINOX) prior to the start of receiving their first dose (Day 1) of study intervention (ponsegromab or placebo). Day 1 study intervention must be taken on the same day participants start their next cycle of nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy and prior to receiving chemotherapy. All chemotherapy dosing is to be determined by the participant's health care provider in accordance with local guidelines. Study intervention will be administered Q4W SC.

Following enrollment completion of Phase 2b, Phase 3 enrollment will begin, and eligible participants will be randomized in a 1:1:1 allocation to study intervention (one of the two doses of ponsegromab, or placebo). Participants must have completed their first-line pre-randomization systemic chemotherapy (1 x 28-day cycle of nab-paclitaxel and gemcitabine or 2 x 14-day cycles of FOLFIRINOX) prior to the start of receiving their first dose (Day 1) of study intervention (ponsegromab or placebo). Day 1 study intervention must be taken on the same day participants start their next cycle of nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy and prior to receiving chemotherapy. All chemotherapy dosing is to be determined by the participant's health care provider in accordance with local guidelines. Study intervention will be administered Q4W SC.

Once all Phase 2b participants have completed Week 12 procedures, an analysis of Phase 2b will be performed, from which one of the 2 ponsegromab doses will be selected. After the Phase 3 ponsegromab dose has been selected, continuing Phase 2b participants will:

* Continue the ponsegromab dose selected for Phase 3 if already randomized to that dose, OR

* Be switched to the ponsegromab dose selected for Phase 3 if randomized to the non-selected ponsegromab dose, OR

* Continue receiving placebo if randomized to placebo

* Remain blinded to study treatment

After the ponsegromab dose has been selected, continuing Phase 3 participants will:

* Continue the ponsegromab dose selected for Phase 3 if already randomized to that dose, OR

* Be switched to the ponsegromab dose selected for Phase 3 if randomized to the non-selected ponsegromab dose, OR

* Continue receiving placebo if randomized to placebo

* Remain blinded to study treatment Phase 3 participants enrolled after dose selection will be randomized 1:1 (ponsegromab selected dose: placebo). Participants must have completed their first-line pre-randomization systemic chemotherapy (1 x 28-day cycle of nab-paclitaxel and gemcitabine or 2 x 14-days cycles of FOLFIRINOX) prior to the start of receiving their first dose (Day 1) of study intervention (selected Phase 3 ponsegromab dose or placebo). Day 1 study intervention must be taken on the same day participants start their next cycle of nab-paclitaxel and gemcitabine chemotherapy or FOLFIRINOX chemotherapy and prior to receiving chemotherapy.

During the Phase 3 portion of the study, there will be an optional sub-study for primary caregivers of participants with cachexia and mPDAC to evaluate the effectiveness of ponsegromab in improving the quality of life and well-being of the primary caregivers.

Study intervention (ponsegromab selected dose or placebo) will continue regardless of chemotherapy treatment until permanent discontinuation of study intervention, withdrawal of consent, death, or the end of the Phase 3 double-blind portion of the study has been reached when the approximate number of overall survival events have been accrued for the Phase 3 analysis of overall survival.

Participants will have tumor assessments performed approximately every 6 to 8 weeks during the double-blind period by blinded, independent, central reader radiologists.

When the number of overall survival events has been accrued to terminate the Phase 3 double-blind portion of the study, active participants can continue in the optional open-label extension where they will receive ponsegromab for up to 12 months.

Primary Outcome Measures

1. Percent change from baseline in body weight for ponsegromab compared to placebo
2. Change from baseline in Functional Assessment of Anorexia/Cachexia Therapy 5-item Anorexia Symptom Scale scores
   Scale consists of five items, each rated 0-4. Total score ranges from 0 (minimum) to 20 (maximum). Higher scores are associated with a better outcome.

Secondary Outcome Measures

1. Change from baseline in non-sedentary physical activity time
   measured by wearable Digital Health Technology watch
2. Overall survival
   Outcome defined as the time from randomization to occurrence of all-cause death
3. Change from baseline in body weight (kg)
4. Change from baseline at Week 12 in physical activity as measured by total vector magnitude
   measured by wearable Digital Health Technology watch
5. Effect on progression free survival
   determined by Blinded Independent Central Review
6. Effect on objective response rate
   determined by Blinded Independent Central Review
7. Effect on disease control rate
   determined by Blinded Independent Central Review
8. Effect on duration of response
   determined by Blinded Independent Central Review
9. Change from baseline in skeletal muscle area and radiodensity at third lumbar vertebra (L3)
   measured by CT (or MRI) scan
10. Change from baseline in intermuscular adipose area and radiodensity at L3
    measured by CT (or MRI) scan
11. Change from baseline in subcutaneous adipose area and radiodensity at L3
    measured by CT (or MRI) scan
12. Change from baseline in visceral adipose area and radiodensity at L3
    measured by CT (or MRI) scan
13. Number of participants with incidence of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Adverse Events (AEs) leading to permanent discontinuation from study intervention or from study.
14. Number of participants with laboratory test abnormalities.
15. Number of participants with vital signs abnormalities.
16. Change in physical function, assessed on participant completed Patient-Reported Outcomes Measurement Information System Physical Function (version 8c) questionnaire.
    The overall score range for the T-score is 0-100. Higher scores indicate better outcome.
17. Change in fatigue, as assessed on participant completed Patient-Reported Outcomes Measurement Information System - Fatigue (version 7a) questionnaire.
    The overall score range for the T-score is 29.4-83.2. Lower scores indicate better outcome.
18. Occurrence and severity of symptomatic AEs including diarrhea, nausea, vomiting, decreased appetite, fatigue and mouth sores by maximum grade as assessed by the NCI PRO CTCAE.
19. Change from baseline on ECOG PS
20. Occurrence of chemotherapy dosing changes (including dosing reductions, dosing interruptions, and dosing discontinuations) due to occurrence of the TEAEs of nausea, vomiting, diarrhea, loss of appetite, or fatigue
21. Tumor status
    Assessment of tumor response to treatment as determined by Blinded Independent Central Review assessment per RECIST 1.1 using CT scan (or MRI)