Adult Soft Tissue Sarcoma Clinical Trials

• Male or female age ≥ 18 years at the time of informed consent.

• Be capable, willing, and able to provide written informed consent.

• Be willing to comply with clinical trial instructions and requirements, including tumor biopsies (if feasible and required per protocol).

• Patients must have a locally advanced or metastatic cancer, a malignant solid tumor that has progressed on at least one line of systemic therapy or for which no standard treatment is available, the participant is intolerant to available treatment, or the participant declined standard of care systemic therapy.

• In the dose escalation phase study patients with the following tumor types will be eligible: Of note patients who declined or were intolerable of standard of care systemic therapy will be considered in all dose expansion cohorts.

• Head and neck squamous cell carcinoma (HNSCC)

• Participants must have histologically or cytologically confirmed recurrent and/or metastatic HNSCC and must have received 1-2 prior lines of systemic anti-cancer therapy including a checkpoint inhibitor (patients treated initially with immune checkpoint blockade alone followed by the addition of other drugs in combination \[i.e., cytotoxic chemotherapy or EGFR inhibitor\], will be considered 1 line of therapy.

• HPV positive (p16 IHC positive or HPV RNA ISH positive), PD-L1 CPS score high (≥1)

• HPV negative (p16 IHC negative or HPV RNA ISH negative), PD-L1 CPS score high (≥1)

• Adenoid cystic carcinoma (ACC)

• Participants must have histologically or cytologically confirmed recurrent and/or metastatic ACC (cancers arising from non-salivery gland primary sites are eligible) and may have received none or up 2 prior lines of systemic anti-cancer therapy.

• Merkel cell carcinoma (MCC)

• Participants must have histologically or cytologically confirmed recurrent and or metastatic MCC and must have received at least one but no more than 3 prior lines of systemic anti-cancer therapy including a checkpoint inhibitor and may not have received prior chemotherapy for MCC.

• Monotherapy alone

• Radiation therapy

• Patients will receive palliative radiation therapy to a tumor site if they have at least one other site of measureable disease that can be chosen as the target lesion to assess response to investigational therapy.

• Sarcoma that has demonstrated clinical benefit or an objective response to immune checkpoint blockade or sarcoma subtypes that are considered immunogenic subtypes including but not limited to undifferentiated pleomorphic (UPS) or myxofibrosarcoma (MFS), angiosarcoma, alveolara soft part sarcoma, or undifferentiated sarcoma will be considered.

• Melanoma

• Uveal Melanoma

• Participants must have histologically or cytologically confirmed recurrent and/or metastatic uveal melanoma and received at least one but no more than two prior lines of systemic anti-cancer therapy including tebentafusp (if HLA-A 02:01+, unless patient declined or was deemed ineligible) and/or immune checkpoint inhibitor. Melphalan PHP will count as a line of therapy if give on its own. Unlimited partial hepatic directed therapy will be permitted.

• Mucosal and Acral melanoma

• Participants must have histologically or cytologically confirmed recurrent and/or metastatic mucosal or acral melanoma and received at least one but no more than two prior lines of systemic anti-cancer therapy including prior exposure to immune checkpoint inhibition. Patients treated with BRAF-MEK therapy may have up to 3 prior lines of therapy.

• Non small cell lung cancer

• Participants must have histologically or cytologically confirmed locally advanced/metastatic non-small cell lung cancer with prior exposure to immune checkpoint inhibition and received at least one but no more than 2 prior lines of systemic anti-cancer therapy.

• Participants must have histologically or cytologically confirmed locally advanced/metastatic sarcoma and must have received at least one but no more than 2 prior lines of systemic anti-cancer therapy. Patients will receive palliative radiation therapy to a tumor site if they have at least one other site of measureable disease that can be chosen as the target lesion to assess response to investigational therapy

• Adequate performance status: ECOG 0 or 1/KPS 100-70%.

• Life expectancy of at least three months after the first CRD3874 infusion, according to the Investigator's opinion

• Presence of measurable disease per RECIST v1.1.Target lesion(s) must not be chosen from a previously irradiated field unless there has been radiographically and/or pathologically documented tumor progression in that lesion prior to enrollment.

• In the dose expansion phase , participants must agree to have a pretreatment tumor biopsy for research purposes. Participants in whom biopsy is technically not feasible or in whom the associated procedure would result in unacceptable risk, in the opinion of the Investigator, or patients who do not wish to have a biopsy, archival tissue (most recently procured sample where tissue is available) may be used instead, if available.

• In the dose expansion phase , participants must agree to on-treatment tumor biopsy for research purposes. Participants in whom biopsy is technically not feasible or in whom would result in unacceptable risk, in the opinion of the Investigator, or patients who do not wish to have a biopsy- may be exempted from the biopsy requirement with discussion with the Principal Investigator .

• Female subject of childbearing potential (defined as a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy or who has not been naturally postmenopausal for at least 24 consecutive months) should have a negative serum pregnancy testing at screening visit and within 72 hours prior to the first dose of study medication.

• Adequate organ function determined within 14 days of treatment initiation, defined as follows:

‣ Hemoglobin ≥ 9.0 g/dL

⁃ Absolute neutrophil count ≥ 1,000/mm\^3 (1.0 x 10\^9/L)

⁃ Platelet count ≥ 100,000/mm3 (100 x 10\^9 /L)

⁃ Serum bilirubin ≤ 1.2x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin level \> 1.2x ULN

⁃ Aspartate aminotransferase (AST) ≤ 2.5x ULN OR ≤ 5x ULN for participants with liver metastases

⁃ Alanine aminotransferase (ALT) ≤ 2.5x ULN OR ≤ 5x ULN for participants with liver metastases

⁃ Albumin ≥ 2.5mg/dL.

⁃ Calculated creatinine clearance (CrCl) ≥ 50 mL/min by Cockcroft-Gault formula or CKD-EPI 2021

⁃ International Normalized Ratio (INR) or prothrombin time (PT) ≤1.5x ULN unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants.

⁃ Activated partial thromboplastin time (aPTT) ≤ 1.5x ULN unless participant is receiving anticoagulant therapy as long as PT and PTT is within therapeutic range of intended use of anticoagulants

⁃ Left ventricular ejection fraction (LVEF) \> 50%, as measured by echocardiogram (2D-ECHO) or multi-gated acquisition scan (MUGA)