An Open-Label Phase 1 Dose-Escalation and Expansion Study Investigating the Safety, Pharmacokinetics, Pharmacodynamics, and Activity of PRTH-101 Alone or in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors

The goal of this Open-Label Study is to evaluate the safety and tolerability of PRTH-101 alone or in combination with pembrolizumab in adults with advance or metastatic solid tumors.

PRTH-101 is a therapeutic antibody that specifically binds to and blocks DDR1, a protein expressed on tumor cells that binds collagen to make a minimally permeable physical barrier that blocks immune cells from interacting with and attacking tumor cells. These “immune cell-excluded” solid tumors are resistant to attack by the immune system (as well as other existing therapies). By disabling DDR1, the collagen fibers lose alignment and loosen, creating gaps in the tumor barrier, thus allowing T-cells to enter and naturally attack the tumor.

The main question[s] it aims to answer are:

* to evaluate the safety and tolerability of PRTH-101 as mono therapy and in combination with pembrolizumab,
* to determine the recommended Phase 2 dose as mono therapy and in combination with pembrolizumab,
* to evaluate anti-tumor activity of PRTH-101 as mono therapy and in combination with pembrolizumab in selected indications

Sex: ALL
Minimum Age: 18 Years
Healthy Volunteers: No
Age Groups: ADULT, OLDER_ADULT

Inclusion Criteria:

1. Subject must be willing and able to read, understand, and sign an Informed Consent Form.
2. Subject must be age ≥18 years.
3. Subject has metastatic or advanced, unresectable malignancy and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed at Screening, excluding hepatocellular carcinoma, sarcomas, and gliomas.
4. Subject has a pathologically documented advanced/unresectable or metastatic cancer that is refractory to or intolerable to or the subject is unwilling or ineligible to receive standard treatment known to confer benefit or for which no standard treatment is available.
5. Subject must have an Eastern Cooperative Oncology Group performance status (PS) 0-1.
6. Subject must have a predicted life expectancy of ≥3 months.
7. Subject must have the following laboratory values (obtained ≤14 days prior to enrollment):

1. Calculated creatinine clearance must be ≥30 mL/min by Cockcroft-Gault formula calculation
2. Total bilirubin ≤1.5 × ULN unless has known history of Gilbert’s syndrome (in which case, total bilirubin must be ≤3 × ULN)
3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 × ULN, or ≤3 x ULN in the presence of liver metastases
4. Hemoglobin ≥9.0 g/dL
5. Platelets ≥100 × 109 cells/L 9
6. Absolute neutrophil count ≥1.5 ×10 cells/L (without the use of hematopoietic growth factors)
7. Corrected QT interval (QTc) ≤470 milliseconds (as calculated by the Fridericia correction formula)
8. Women of child-bearing potential (WOCBP) must have a negative pregnancy test within 3 days prior to first administration of PRTH-101.
9. WOCBP and males with female partners of child-bearing potential must agree to use adequate birth control throughout their participation and for 90 days following the last dose of PRTH-101.
10. Subject must be willing to adhere to the study visit schedule and the prohibitions and restrictions specified in this protocol.
11. Subject must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution’s guidelines or have archived tissue available (Section 12.3) at enrollment.

a. Subjects with sites of disease not amenable to biopsy may be considered after discussion with the Sponsor.
12. The subject is not enrolled in any other clinical trial and is not receiving other therapy directed at their malignancy.
13. The subject is willing to undergo pre-and post-treatment skin biopsies.

Exclusion Criteria:

1. Subject has received prior treatment with systemic agents, including, but not limited to, radio-immunoconjugates, antibody-drug conjugates, immune/cytokines, and monoclonal antibodies (e.g., checkpoint inhibitors) within 28 days or five half-lives of the drug, whichever is shorter.
2. Subject has ongoing toxicity from prior therapy >Grade 1 according to the CTCAE, with the following exceptions. Such exceptions must be assessed by the Investigator (and approved by the Sponsor) as not placing the subject at undue safety risk from participating in this study.

1. Alopecia, and vitiligo
2. Grade ≤2 neuropathy
3. Well-controlled hypo/hyperthyroidism or other endocrinopathies that are well controlled with hormone replacement
3. Subject has undergone a major surgery (excluding minor procedures e.g., placement of vascular access) <2 months prior to administration of PRTH-101.
4. Subject has received radiation therapy 30 days prior to administration of PRTH-101).
15. Women who are pregnant or breastfeeding.
16. History of any of the following ≤6 months before first dose:

a. Congestive heart failure New York Heart Association Grade III or IV b. Unstable angina c. Myocardial infarction d. Unstable symptomatic ischemic heart disease e. Uncontrolled hypertension despite appropriate medical therapy f. Ongoing symptomatic cardiac arrhythmias of > Grade 2 g. Symptomatic cerebrovascular events, or any other serious cardiac condition (e.g., pericardial effusion or restrictive cardiomyopathy); chronic atrial fibrillation on stable anticoagulant therapy is allowed.
17. Subject has any contraindications to the imaging assessments or other study procedures that subjects will be undergoing.
18. Subject has any medical or social condition that, in the opinion of the Investigator, might place a subject at increased risk, affect compliance, or confound safety or other clinical study data interpretation.