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.

• Change from baseline in non-sedentary physical activity time [Срок оценки: Baseline, Week 12]
• Overall survival [Срок оценки: Randomization through completion of Phase 3 of the study, an average of 1 year]
• Change from baseline in body weight (kg) [Срок оценки: Baseline, Week 12 and up to Week 52]
• Change from baseline at Week 12 in physical activity as measured by total vector magnitude [Срок оценки: Baseline, Week 12]
• Effect on progression free survival [Срок оценки: Randomization through completion of Phase 3 of the study, an average of 1 year]
• Effect on objective response rate [Срок оценки: Baseline, Week 52]
• Effect on disease control rate [Срок оценки: Baseline, Week 52]
• Effect on duration of response [Срок оценки: Baseline, Week 52]
• Change from baseline in skeletal muscle area and radiodensity at third lumbar vertebra (L3) [Срок оценки: Baseline, Week 12]
• Change from baseline in intermuscular adipose area and radiodensity at L3 [Срок оценки: Baseline, Week 12]
• Change from baseline in subcutaneous adipose area and radiodensity at L3 [Срок оценки: Baseline, Week 12]
• Change from baseline in visceral adipose area and radiodensity at L3 [Срок оценки: Baseline, Week 12]