A Study of SGN-MesoC2 in Advanced Solid Tumors

Inclusion Criteria:

• An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

• Participants must have histologically- or cytologically-confirmed metastatic orlocally advanced unresectable ovarian cancer, non-small cell lung cancer (NSCLC),pancreatic adenocarcinoma, endometrial cancer (EC), colorectal cancer (CRC),mesothelioma.

• Must have at least one measurable lesion at baseline based on RECIST v1.1.

• Archival tumor tissue is required, or, if unavailable, a fresh tumor biopsy (if itis safe and feasible) during the screening period.

• Participants weighing ≥40 kg

• Additional inclusion criterion for platinum resistant ovarian cancer (PROC)participants: Histologically or cytologically documented invasive epithelialovarian, primary peritoneal, or fallopian tube cancer (tumors with pseudomyxomatousor mucinous histology are excluded) or advanced predominantly epithelioidperitoneal, must have relapsed or progressed following local standard therapies orfor which no standard therapy is available.

• Platinum prior exposure unless it is contraindicated or not available.

• Participants with known FRa high expression, must have progressed after mirvetuximabsoravtansine or other FRa-directed therapy) unless contraindicated or not available.Participants whose cancer is associated with homologous recombination deficiency (HRD)-positive status must have been exposed to PARP inhibitors, unlesscontraindicated or not available.

• Additional inclusion criterion for pancreatic ductal adenocarcinoma (PDAC)participants (Part A only): Histologically or cytologically documented, locallyadvanced unresectable or metastatic pancreatic adenocarcinoma, including recurrenceof previously resected disease.

• Participant must have progressed after standard cytotoxic therapies, or for which nostandard therapy is available. Participants must have received fluoropyrimidine-,oxaliplatin-, and irinotecan-based chemotherapy, gemcitabine and nab-paclitaxelcombination or gemcitabine-based chemotherapy.

• Additional inclusion criterion for NSCLC participants (Part A only): Histologicallyor cytologically confirmed advanced and/or metastatic NSCLC, must have progressedafter standard therapies, or for which no standard therapy is available.

• Participants do not need to have expression of MSLN in tumor to be selected for PartC enrollment unless retrospective analysis of the immunohistochemistry (IHC) data indose escalation suggests it as a requirement.

• a. If participants have a specific mutation for which standard therapy is available (eg, ALK, ROS1, MET, NTRK, BRAF V600E, EGFR Exon 20 ins, RET, KRAS G12C, HER2), theymust have documented progression after treatment with appropriate tyrosine kinaseinhibitor or other agent and have documented progression after platinum doubletchemotherapy treatment, unless not tolerated, contraindicated, or not available.

• b. If participants do not have a specific mutation for which standard therapy isavailable, they must have documented progression after treatment with a check pointinhibitor and platinum based chemotherapy, unless not tolerated, contraindicated, ornot available.

• Additional inclusion criterion for CRC participants (Part A only): Histologicallyconfirmed metastatic or locally advanced colorectal adenocarcinoma.

• Participant must have progressed after standard therapy, or for which no standardtherapy is available. Participants must have received fluoropyrimidine-,oxaliplatin-, and irinotecan-based chemotherapy, unless not tolerated,contraindicated, or not available.

• Participants with microsatellite instability (MSI)-H/mismatch repair deficient (dMMR) tumors must have received treatment with a PD-1 mAb, unless not tolerated oravailable. If participants have an BRAF mutation or other mutations, they must havedocumented progression after treated with appropriate therapies (eg, encorafenib +cetuximab), unless not tolerated or available. Particpants with HER2 positivetumors, must have received treatment with HER2-directed therapies (eg, tucatinib +trastuzumab), unless not tolerated or available.

• Participants do not need to have expression of MSLN in tumor to be selected for PartC enrollment unless retrospective analysis of the IHC data in dose escalationsuggests it as a requirement.

• Additional inclusion criteria for EC participants (Part A only): Participant musthave received at least 1 line of platinum-based chemotherapy.

• Participant must have received up to 2 lines of systemic therapy in metastaticsetting.

• If appropriate by biomarker status (including but not limited to microsatelliteinstability [MSI] and dMMR status) and available per local SOC, must have received aprior PD-1 inhibitor and/or the combination of pembrolizumab and lenvatinib, unlessnot tolerated.

• Additional inclusion criteria for mesothelioma participants (Part A only):Histologically or cytologically confirmed advanced and/or metastatic mesothelioma,must have progressed after standard therapies, or for which no standard therapy isavailable.

• Additional inclusion criteria for all tumor types (Parts B and C only): Participantsmust have histologically- or cytologically-confirmed metastatic or locally advancedunresectable ovarian cancer, non-small cell lung cancer (NSCLC), pancreaticadenocarcinoma, endometrial cancer (EC), colorectal cancer (CRC), or mesothelioma.

• Participants must not have received more than 2 lines of cytotoxic systemic therapyin metastatic setting.

Exclusion Criteria:

• Participants previously received or is currently receiving the following anticancermedications or investigational drugs will be excluded:

• Any systemic anticancer therapy or focal radiotherapy within 4 weeks prior tofirst dose of PF-08052666or within 2 weeks prior to the first dose ofPF-08052666if the underlying disease has progressed on treatment.

• For Part C, prior anti-Mesothelin (MSLN) antibody (mAb or BsAb), MSLN- directedADC.

• Major surgery (excluding placement of vascular access) within 4 weeks, or minorsurgery within 7 days, prior to first dose of study intervention.

Participants must have recovered adequately from the toxicity or complications from the surgery prior to starting PF-08052666. Participants who have planned major surgery during the treatment period must be excluded from the study.

• History of another malignancy within 3 years before the first dose of studyintervention, or any evidence of residual disease from a previously diagnosedmalignancy. Exceptions are malignancies with a negligible risk of metastasis ordeath.

• Known to be positive for human immunodeficiency virus (HIV). Participants withsevere or uncontrolled systemic diseases, including uncontrolled hypertension,uncontrolled diabetes mellitus, or active bleeding diatheses.

• Participants with medical history of clinically significant lung diseases (eg,interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiationpneumonitis) or who are suspected to have these diseases by imaging at screeningperiod.

• Previously untreated brain metastases. Participants who have received radiation orsurgery for brain metastases are eligible if therapy was completed at least 4 weeksprior to initiation of study treatment, there is no evidence of central nervoussystem (CNS) disease progression, and there is no requirement for chroniccorticosteroid therapy. Leptomeningeal metastases or spinal cord compression due todisease.