Contract analysis

1. Sponsor Information Sponsor: Penterra Pharmaceuticals Corp. ("Penterra" or "PPC") Principal Office Address: 200 Biopharma Boulevard, Suite 1400, Princeton, New Jersey 08540 Entity Type: Penterra Pharmaceuticals Corp. is a corporation organized and existing under the laws of the State of Delaware. Penterra is publicly traded on the Nasdaq Global Select Market under the ticker symbol "PTRA." IND Holder: Penterra Pha

2. Investigational Product Generic Name: Penterafenib Compound Designation: PPC-4871 Drug Class: Penterafenib is classified as a next-generation oral multi-kinase inhibitor. It belongs to a class of small-molecule compounds designed to selectively inhibit multiple kinase targets that play critical roles in the proliferation, survival, and angiogenesis pathways implicated in hepatocellular carcinoma and other solid tu

3. Study Title and Protocol Identification Full Protocol Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy and Safety of Penterafenib (PPC-4871) Versus Placebo in Patients with Advanced Hepatocellular Carcinoma Who Have Progressed on or After Prior Systemic Therapy (CLARION) Protocol Short Title: CLARION — Clinical Assessment of Response with Longitudinal In

4. Study Rationale and Background Hepatocellular carcinoma ("HCC") is the most common form of primary liver cancer, accounting for approximately 75% to 85% of all primary liver malignancies. HCC represents a significant and growing public health burden worldwide and is among the leading causes of cancer-related mortality globally. The incidence of HCC has increased substantially over the past several decades, driven

5. Study Objectives 5.1 Primary Objective The primary objective of the CLARION trial is to evaluate the effect of penterafenib (PPC-4871) on overall survival ("OS") compared to placebo in patients with advanced hepatocellular carcinoma who have progressed on or after at least one prior line of systemic therapy. The primary objective is intended to determine whether treatment with penterafenib provides a statistically

1. To evaluate the effect of penterafenib on progression-free survival ("PFS") compared to placebo, where PFS is defined as the time from randomization to first documented radiographic disease progression per RECIST v1.1 or death from any cause, whichever occurs first.

2. To assess the objective response rate ("ORR") per RECIST v1.1 criteria, defined as the proportion of randomized subjects who achieve a confirmed complete response ("CR") or partial response ("PR") as their best overall response.

3. To evaluate the duration of response ("DOR") in subjects who achieve an objective response (CR or PR), defined as the time from first documented response to first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first.

4. To characterize the safety and tolerability profile of penterafenib in the study population, including the incidence, severity, and relationship of adverse events and serious adverse events, laboratory abnormalities, dose modifications, and treatment discontinuations. 5.3 Exploratory Objectives The exploratory objectives of the CLARION trial include:

1. To explore biomarkers that may be predictive of response to penterafenib, including, but not limited to, genomic, proteomic, and circulating biomarkers that may identify patient subpopulations most likely to benefit from treatment.

2. To assess patient-reported outcomes ("PROs") and health-related quality of life ("HRQoL") using validated instruments administered at protocol-specified intervals, in order to evaluate the effect of penterafenib on patient-centered measures of benefit.

3. To pharmacokinetic ("PK") parameters of penterafenib, including plasma concentration-time profiles, in the study population, and to assess pharmacodynamic ("PD") parameters that may inform the relationship between drug exposure, target modulation, and clinical outcomes.

6. Study Design Phase: Phase III Design: The CLARION trial is a randomized, double-blind, placebo-controlled, multi-center, parallel-group study designed to evaluate the efficacy and safety of penterafenib (PPC-4871) compared to placebo in patients with advanced hepatocellular carcinoma who have progressed on or after at least one prior line of systemic therapy. Randomization Ratio: Eligible subjects will be randomiz

7. Study Population 7.1 Target Population The target population for the CLARION trial consists of adult patients (aged eighteen [18] years or older) with histologically or cytologically confirmed advanced (unresectable or metastatic) hepatocellular carcinoma who have progressed on or after, or who are intolerant to, at least one prior line of systemic therapy for advanced HCC. This patient population represents an ar

1. Histologically or cytologically confirmed diagnosis of hepatocellular carcinoma.

2. Advanced disease, defined as unresectable or metastatic hepatocellular carcinoma not amenable to curative surgical resection, liver transplantation, or local therapies with curative intent.

3. Documented radiographic disease progression on or after, or documented intolerance to, at least one prior line of systemic therapy for advanced hepatocellular carcinoma. Prior systemic therapy may include, but is not limited to, immune checkpoint inhibitor-based regimens, tyrosine kinase inhibitors, or anti-angiogenic agents.

4. Measurable disease per RECIST v1.1, with at least one measurable target lesion that has not been previously treated with local therapy (or, if previously treated, has demonstrated unequivocal radiographic progression since the local therapy).

5. Child-Pugh liver function classification of Class A (score 5–6) at screening.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.

7. Adequate organ function as defined by protocol-specified laboratory parameters, including adequate hematologic, hepatic, renal, and coagulation function.

8. Estimated life expectancy of at least twelve (12) weeks as assessed by the investigator.

9. Written informed consent obtained from the subject (or the subject's legally authorized representative, if applicable) prior to the performance of any study-related procedures, in accordance with applicable regulatory requirements and institutional policies. 7.3 Key Exclusion Criteria (Summary) The following is a summary of the key exclusion criteria for the CLARION trial. The complete and definitive exclusion cri

1. Prior treatment with penterafenib (PPC-4871) or any investigational kinase inhibitor with an identical or substantially similar mechanism of action to penterafenib.

2. Known fibrolamellar variant of HCC, sarcomatoid HCC, or mixed hepatocholangiocarcinoma histology.

3. Active or untreated brain metastases or leptomeningeal disease. Subjects with previously treated and clinically stable brain metastases (defined as no evidence of progression for at least four [4] weeks prior to screening and no requirement for systemic corticosteroids at doses exceeding the equivalent of prednisone 10 mg/day) may be eligible, as specified in the full protocol.

4. Clinically significant cardiovascular disease, including, but not limited to, uncontrolled hypertension, symptomatic congestive heart failure (New York Heart Association Class III or IV), unstable angina pectoris, myocardial infarction within six (6) months prior to randomization, or clinically significant cardiac arrhythmia requiring treatment.

5. Uncontrolled hepatitis B virus (HBV) infection (defined as HBV DNA exceeding protocol-specified thresholds) or uncontrolled hepatitis C virus (HCV) infection (defined as detectable HCV RNA). Subjects with controlled HBV infection on appropriate antiviral therapy may be eligible, as specified in the full protocol.

6. History of prior organ transplantation, including liver transplantation.

7. Pregnancy or breastfeeding. Female subjects of childbearing potential must have a negative pregnancy test at screening and must agree to use highly effective contraception throughout the study and for the protocol-specified period following the last dose of study treatment.

8. Other exclusion criteria as specified in the full protocol, including conditions that would, in the judgment of the investigator, preclude safe participation in the study or interfere with the interpretation of study results.

8. Planned Enrollment and Study Sites Total Planned Enrollment: The CLARION trial will enroll a total of one thousand two hundred (1,200) subjects globally. Of these, subjects enrolled at sites within the Veridian Health Research Network will constitute a substantial portion of the overall enrollment, as described below and in the MCTA. Randomization: Subjects will be randomized in a 2:1 ratio, with eight hundred (80

9. Principal Investigators Global Principal Investigator: Dr. Catherine Aldridge, M.D., Ph.D., serves as the Global Principal Investigator for the CLARION trial. Dr. Aldridge is a Professor of Oncology at Graystone University Medical Center and holds board certification in Medical Oncology and Hematology from the American Board of Internal Medicine. Dr. Aldridge has extensive experience in the conduct of registration

10. Study Endpoints 10.1 Primary Endpoint Overall Survival (OS): The primary endpoint of the CLARION trial is overall survival, defined as the time from the date of randomization to the date of death from any cause. Subjects who are alive at the time of the analysis data cutoff or who are lost to follow-up will be censored at the date of last known contact. Overall survival was selected as the primary endpoint becaus

11. Study Duration and Timeline Projected Total Study Duration: The total projected duration of the CLARION trial is approximately sixty (60) months (five [5] years), from the date of the first patient's enrollment through the completion of the final study activities, including the survival follow-up period. The projected study timeline is composed of the following phases: • Enrollment Period: Approximately forty-two

12. Study Treatment 12.1 Investigational Product Subjects randomized to the treatment arm will receive penterafenib (PPC-4871) oral film-coated tablets, administered once or twice daily at the dose and schedule specified in the full protocol (Protocol PPC-4871-III). The specific dose level, dosing frequency, dose modification guidelines (including criteria for dose reductions, dose interruptions, and dose discontinua

13. Study Assessments (Summary) 13.1 Efficacy Assessments Tumor assessments will be performed using computed tomography (CT) or magnetic resonance imaging (MRI) in accordance with RECIST v1.1 criteria. The imaging modality used at baseline for each subject should be used consistently throughout the study to ensure comparability of assessments. The schedule of tumor assessments is as follows: • Baseline: Tumor assessm

14. Study Visits and Milestone Schedule The following table summarizes the key study visits and the associated per-patient milestone payment triggers under the MCTA: Total Per-Patient Site Fee: The total per-patient site fee under the MCTA is fifty-two thousand dollars ($52,000) per enrolled subject, payable in four (4) equal milestone installments of thirteen thousand dollars ($13,000) each. Milestone payments are t

15. Data Management and Electronic Data Capture EDC Platform Provider: Pinnacle Data Solutions, Inc. ("Pinnacle"), located at 6000 Clearwater Drive, San Diego, California 92121, has been engaged by Penterra to provide the electronic data capture ("EDC") and eClinical platform for the CLARION trial. The Pinnacle EDC system has been validated in accordance with applicable regulatory requirements and industry standards.

16. Safety Reporting Serious Adverse Event (SAE) Reporting: Participating sites are required to report all serious adverse events to Penterra (via the Meridian CRO safety reporting system) within twenty-four (24) hours of the investigator becoming aware of the event. An SAE is defined as any adverse event that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospit

17. Statistical Considerations (Summary) Sample Size Rationale: The CLARION trial will enroll a total of one thousand two hundred (1,200) subjects, randomized in a 2:1 ratio to penterafenib (n=800) or placebo (n=400). The sample size has been calculated to provide adequate statistical power to detect a clinically meaningful improvement in overall survival in the penterafenib arm compared to the placebo arm. The speci

18. Regulatory Framework The CLARION trial will be conducted in compliance with all applicable United States federal regulations, international guidelines, and institutional requirements governing the conduct of clinical trials involving investigational new drugs. The following regulatory framework applies: Applicable Regulations: • 21 C.F.R. Part 312 — Investigational New Drug Application. Penterra, as the IND holde

19. Informed Consent Written informed consent is required from all subjects (or, where applicable, from a subject's legally authorized representative in accordance with applicable state law and institutional policy) prior to the performance of any study-related procedures, including screening assessments. The informed consent process is a fundamental ethical and regulatory requirement for the conduct of this clinical

20. Study Governance and Oversight Sponsor Oversight: Penterra Pharmaceuticals Corp. retains overall responsibility for the design, conduct, and oversight of the CLARION trial. The Penterra clinical development and operations teams, led by Dr. Marcus Yun, M.D., M.P.H. (Senior Vice President, Clinical Development) and Jennifer Holt (Vice President, Clinical Operations), will provide ongoing oversight of all aspects of

21. Confidentiality and Data Ownership All protocol-related information, investigational product specifications, preclinical and clinical data, study results, and other information generated in connection with the CLARION trial constitute confidential information of Penterra Pharmaceuticals Corp. Such information is subject to the ten (10)-year confidentiality term set forth in Exhibit F to the MCTA between Penterra

22. Publication Policy Investigators participating in the CLARION trial may publish or present the results of the study in peer-reviewed journals, at scientific conferences, or in other academic forums, subject to the terms and conditions set forth in Exhibit G to the MCTA. Prior to any publication or presentation, investigators must submit a complete copy of the proposed publication or presentation materials to Pent