This Phase I/II study is studying the dose levels, safety and effectiveness of a new targeted therapy (Modakafusp Alfa) alone, and in combination with immunotherapy (pembrolizumab), in adults with advanced or metastatic solid cancersAn Open-Label, Dose-Escalation Phase 1b/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Modakafusp Alfa (TAK-573) as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Advanced or Metastatic Solid Tumors

Inclusion

1. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
2. For both the dose escalation and expansion cohort phases of the study, eligible participants must have histologically confirmed advanced (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors.
3. Measurable disease per RECIST v1.1. At least 1 target lesion amenable for biopsy is required for enrollment in phase 1b. A minimum of 1 target lesion for response assessment is required for enrollment in phase 2. A separate lesion amenable for biopsy is required for enrollment in phase 2 for cohorts I and II post futility analysis and for all participants (safety lead-in and expansion) with subgroup III melanoma.
4. Phase 1b Dose Escalation: Participants with histologically confirmed advanced locally (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors.

Phase 2 Dose Expansion:

The combination cohorts, including participants in the safety-lead phase, will enroll participants with unresectable/metastatic melanoma in the following subgroups:

I. Unresectable/metastatic histologically confirmed cutaneous melanoma with primary resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting.

II. Unresectable/metastatic histologically confirmed cutaneous melanoma with acquired resistance to no more than 2 prior lines of anti-PD1 containing treatments in the metastatic setting.

III. Unresectable/metastatic histologically confirmed cutaneous melanoma naive to prior anti-PD1 containing treatments in the metastatic setting.

• Participants with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy.
• For the expansion cohorts I and II, there is no limitation of total number of prior line(s) of therapy, but the number of prior line(s) containing anti-PD1 must be ≤2 in the metastatic setting.
• For the expansion cohort III, participants who received an anti-PD-1 treatment in the adjuvant setting must have completed that treatment at least 6 months prior to enrollment and must not have progressed on the anti-PD1 adjuvant treatment.
• Primary resistance is defined as a best response of PD or SD less than (<) 6 months to an anti-PD1 alone or in combination with other agents (that is, CTLA4) in the initial anti-PD1 containing treatment.
• Acquired resistance is defined as a progression following a best response of CR, PR or SD>6 months to a prior anti-PD1 alone or in combination with other agents (that is, CTLA4).