EXHIBIT A
to the
MASTER CLINICAL TRIAL AGREEMENT
dated June 28, 2023
by and between
PENTERRA PHARMACEUTICALS CORP.
and
VERIDIAN HEALTH RESEARCH NETWORK, INC.
PROTOCOL SYNOPSIS
Protocol Number: PPC-4871-III
CLARION — Clinical Assessment of Response with Longitudinal Investigation in ONcology
IND Number: IND 157823
ClinicalTrials.gov Identifier: NCT05928174
Final Version — June 23, 2023
CONFIDENTIAL AND PROPRIETARY
This document contains confidential and proprietary information of Penterra Pharmaceuticals Corp. ("Penterra" or "PPC"). This document is provided solely for the purpose of evaluating and conducting the clinical trial described herein under the Master Clinical Trial Agreement ("MCTA") between Penterra Pharmaceuticals Corp. and Veridian Health Research Network, Inc. dated June 28, 2023. No part of this document may be reproduced, transmitted, or disclosed to any third party without the prior written consent of Penterra Pharmaceuticals Corp. Unauthorized disclosure, reproduction, or use of this document or its contents is strictly prohibited and may result in liability under the confidentiality provisions of the MCTA. This document is subject to the ten (10)-year confidentiality term set forth in the MCTA and the associated provisions of Exhibit F thereto. Recipients of this document are advised that its contents constitute trade secrets and proprietary business information protected under applicable federal and state law.
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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 Pharmaceuticals Corp. is the holder of Investigational New Drug Application No. IND 157823, filed with the United States Food and Drug Administration ("FDA") in connection with the clinical development of penterafenib (PPC-4871).
The following individuals are designated as key sponsor personnel with respect to the conduct of this study:
Contract Research Organization: Penterra has engaged Meridian Contract Research Organization, Inc. ("Meridian CRO"), with principal offices at 9200 Corporate Boulevard, Raleigh, North Carolina 27615, to serve as the contract research organization for this study. Meridian CRO is responsible for clinical site monitoring (including both on-site and remote monitoring visits), clinical data management, safety reporting and pharmacovigilance operations, and biostatistical analysis, each as set forth in the Master Services Agreement between Penterra and Meridian CRO dated January 15, 2023 (the "CRO MSA"). All obligations delegated to Meridian CRO remain the ultimate responsibility of Penterra as the study sponsor under applicable FDA regulations.
FDA Regulatory Counsel: Castleton & Hargrove LLP, 1100 Connecticut Avenue NW, Suite 900, Washington, DC 20036. Lead regulatory counsel for this program is Dr. Priya Sundaram, Esq., a partner in Castleton & Hargrove's FDA Regulatory and Life Sciences Practice Group. Dr. Sundaram serves as primary outside counsel for all IND-related regulatory submissions, FDA interactions, and regulatory strategy matters pertaining to the penterafenib clinical development program.
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 tumor malignancies.
Route of Administration: Oral
Formulation: Penterafenib is formulated as film-coated tablets. Specific dose strengths, including tablet appearance, excipient composition, storage conditions, and packaging configurations, are described in the full protocol and the Investigator's Brochure. Matching placebo tablets, identical in size, shape, color, and appearance to the active investigational product, have been manufactured for use as the control in this double-blind study.
Mechanism of Action: Penterafenib exerts its anti-tumor activity through the selective inhibition of multiple kinase targets that are critically implicated in hepatocellular carcinoma proliferation and tumor-associated angiogenesis. The compound has demonstrated potent inhibition of key signaling cascades that drive tumor cell growth, survival, and vascular supply in preclinical models of HCC. Detailed characterization of the molecular targets, binding affinities, selectivity profiles, and in vitro and in vivo pharmacology data are provided in the current Investigator's Brochure for PPC-4871.
IND Filing Date: The IND application for penterafenib (IND 157823) was filed with the FDA in October 2021. The IND became effective thirty (30) days following submission, and clinical trials under this IND have been conducted continuously since that time.
Current Development Status: As of the date of this Protocol Synopsis, the Phase II clinical program for penterafenib has been completed. The Phase II trial concluded in January 2023 and demonstrated an objective response rate ("ORR") of 38% in patients with advanced hepatocellular carcinoma, as assessed by an independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The Phase II safety and tolerability data, together with the efficacy signal observed, support the advancement of penterafenib into this pivotal Phase III trial. Detailed Phase II results are summarized in the Investigator's Brochure and were the basis for the design of the CLARION study described herein.
Comparator / Control: Matching placebo. The placebo formulation is identical in appearance to the active penterafenib film-coated tablets and is manufactured under the same Good Manufacturing Practice ("cGMP") standards. Placebo tablets contain no active pharmaceutical ingredient.
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 Investigation in ONcology
Protocol Number: PPC-4871-III
IND Number: IND 157823
ClinicalTrials.gov Identifier: NCT05928174
This protocol has been registered on ClinicalTrials.gov in accordance with Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 801) and applicable FDA guidance. The registration record is publicly accessible at www.clinicaltrials.gov under the identifier NCT05928174. Penterra will ensure timely updates to the registration record in accordance with regulatory requirements, including submission of results information within the timeframes specified under 42 U.S.C. § 282(j).
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 by the prevalence of chronic hepatitis B and C infection, non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, and other etiological factors. Despite advances in screening, diagnosis, and first-line systemic treatment, the prognosis for patients with advanced (unresectable or metastatic) HCC remains poor, with a median overall survival typically measured in months for patients who have progressed beyond first-line therapy.
For patients with advanced HCC, first-line systemic therapy options have expanded in recent years with the approval of immune checkpoint inhibitor-based combinations and tyrosine kinase inhibitors. However, the treatment landscape for patients who progress on or after first-line systemic therapy remains limited. Currently available second-line agents have demonstrated modest clinical benefits, with incremental improvements in overall survival on the order of one to three months in pivotal trials. There remains a substantial unmet medical need for effective and well-tolerated therapies in the second-line setting for advanced HCC.
Penterafenib (PPC-4871), a next-generation oral multi-kinase inhibitor developed by Penterra Pharmaceuticals Corp., has been designed to selectively target multiple kinase pathways implicated in HCC tumor proliferation and angiogenesis. In preclinical studies, penterafenib demonstrated potent anti-tumor activity in HCC cell lines and xenograft models, with a favorable selectivity profile that differentiates it from currently available kinase inhibitors in this therapeutic space. The preclinical pharmacology, toxicology, and pharmacokinetic data supporting the clinical development of penterafenib are detailed in the current Investigator's Brochure.
The Phase II clinical program for penterafenib, completed in January 2023, enrolled patients with advanced HCC who had progressed on or were intolerant to at least one prior line of systemic therapy. The Phase II trial demonstrated a 38% objective response rate (ORR), as assessed by independent central review per RECIST v1.1, in this heavily pretreated patient population. This ORR substantially exceeded the response rates historically observed with approved second-line agents in similar patient populations. Additionally, the Phase II data demonstrated a favorable safety and tolerability profile, with adverse events generally manageable through dose modification and supportive care. The Phase II results, taken together with the preclinical data and the strong scientific rationale based on kinase target biology, provide a compelling basis for advancement to a pivotal Phase III trial.
The CLARION trial (Protocol PPC-4871-III) is designed as a randomized, double-blind, placebo-controlled, multi-center Phase III study to evaluate whether penterafenib confers a statistically significant and clinically meaningful improvement in overall survival compared to placebo in patients with advanced HCC who have progressed on or after at least one prior line of systemic therapy. Overall survival has been selected as the primary endpoint because it represents the most definitive measure of clinical benefit in oncology trials and is the standard endpoint expected by regulatory authorities for registration-enabling studies in this indication. The scientific rationale for the study, including the detailed kinase target biology, preclinical efficacy data, and the Phase II clinical results, is provided in the Investigator's Brochure for PPC-4871.
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 significant and clinically meaningful improvement in overall survival in this patient population compared to placebo with best supportive care.
5.2 Key Secondary Objectives
The key secondary objectives of the CLARION trial are as follows:
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 randomized in a 2:1 ratio to one of two treatment arms:
• Treatment Arm (Penterafenib): Eight hundred (800) subjects will be randomized to receive penterafenib (PPC-4871) oral film-coated tablets administered at the dose and schedule specified in the full protocol, in combination with best supportive care.
• Control Arm (Placebo): Four hundred (400) subjects will be randomized to receive matching placebo oral film-coated tablets administered on the same schedule as the investigational product, in combination with best supportive care.
Randomization will be performed centrally through an interactive web response system ("IWRS") managed by Meridian CRO. Each subject will be assigned a unique randomization number upon confirmation of eligibility and completion of all screening procedures.
Blinding: This study is double-blind. Subjects, investigators, site staff (including pharmacists preparing study drug at the site level), sponsor personnel, and CRO staff will be blinded to individual treatment assignments throughout the study. The matching placebo tablets are identical in appearance, size, shape, color, and weight to the active penterafenib tablets to maintain the integrity of the blind. Unblinding of individual treatment assignments will be permitted only in the case of medical emergencies where knowledge of the treatment assignment is essential for the appropriate clinical management of the subject. The procedures for emergency unblinding are specified in the full protocol and involve use of the IWRS emergency unblinding function, with mandatory documentation and notification to the sponsor within twenty-four (24) hours of any unblinding event.
Stratification Factors: Randomization will be stratified by pre-specified factors to ensure balanced treatment assignment across important prognostic categories. The anticipated stratification factors include geographic region (North America vs. Europe vs. Asia-Pacific), etiology of liver disease (viral vs. non-viral), type of prior systemic therapy (immune checkpoint inhibitor-based vs. other), and ECOG performance status (0 vs. 1). The final stratification factors and their categories will be detailed in the full protocol and the statistical analysis plan.
Number of Treatment Arms: Two (2) — penterafenib (PPC-4871) and matching placebo.
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 area of significant unmet medical need, as described in Section 4 of this Protocol Synopsis.
7.2 Key Inclusion Criteria (Summary)
The following is a summary of the key inclusion criteria for enrollment in the CLARION trial. The complete and definitive inclusion criteria are set forth in the full protocol (Protocol PPC-4871-III). In the event of any discrepancy between this synopsis and the full protocol, the full protocol will govern.
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 criteria are set forth in the full protocol. In the event of any discrepancy between this synopsis and the full protocol, the full protocol will govern.
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 (800) subjects assigned to the penterafenib (PPC-4871) treatment arm and four hundred (400) subjects assigned to the matching placebo control arm.
Site Network (under the MCTA): Veridian Health Research Network, Inc. ("Veridian" or "VHRN"), with principal offices at 750 Research Parkway, 8th Floor, Philadelphia, Pennsylvania 19104, serves as the network coordinator and contracting entity for participating clinical trial sites under the MCTA. Veridian is a nonprofit corporation organized under the laws of the Commonwealth of Pennsylvania that coordinates clinical research activities across a network of academic medical centers and affiliated research institutions.
Number of Participating Sites: Thirty-eight (38) Veridian Network academic medical centers and affiliated research institutions located across fourteen (14) states within the United States will participate in the CLARION trial under the MCTA. A complete listing of all participating Veridian Network sites, including site identification numbers, institutional names, addresses, and designated principal investigators, is set forth in Schedule 1 to the MCTA.
Lead Enrollment Site: Graystone University Medical Center, located at 1200 University Avenue, Philadelphia, Pennsylvania 19104, is designated as Site 001 and serves as the lead enrollment site for the CLARION trial within the Veridian Network. Graystone University Medical Center is a major academic medical center with an NCI-designated comprehensive cancer center and extensive experience in the conduct of Phase III oncology clinical trials.
Key Enrollment Site: Lakemont Medical Center, located at 4400 North Michigan Drive, Chicago, Illinois 60611, is designated as Site 002 and serves as a key enrollment site within the Veridian Network. Lakemont Medical Center is a leading academic institution with a nationally recognized hepatology and liver cancer program.
Additional Sites: Additional Veridian Network sites are enrolled into the CLARION trial pursuant to Individual Site Agreements, which take the form of joinder agreements referencing and incorporating the terms and conditions of the MCTA. Each Individual Site Agreement identifies the site-level principal investigator, sub-investigators, key site personnel, and any site-specific terms or requirements. The execution of an Individual Site Agreement by a participating site constitutes that site's agreement to be bound by the applicable provisions of the MCTA.
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 registrational clinical trials in hepatocellular carcinoma and other gastrointestinal malignancies. As Global Principal Investigator, Dr. Aldridge is responsible for overall scientific leadership of the trial, participation in the Steering Committee, and collaboration with the sponsor on protocol design, data interpretation, and publication of study results.
Co-Principal Investigator: Dr. Howard Matsuoka, M.D., serves as the Co-Principal Investigator for the CLARION trial. Dr. Matsuoka is an Associate Professor of Hepatology and Oncology at Lakemont Medical Center, with a clinical and research focus on liver cancer and hepatobiliary malignancies. Dr. Matsuoka will serve as Co-Principal Investigator with responsibility for contributing to the scientific conduct of the trial, participating in the Steering Committee, and providing clinical and scientific guidance as needed.
Site-Level Principal Investigators and Sub-Investigators: Individual principal investigators and sub-investigators at each participating Veridian Network site are identified in the corresponding Individual Site Agreements and in the Form FDA 1572 ("Statement of Investigator") filings submitted to the FDA for each site. Each site-level principal investigator assumes responsibility for the proper conduct of the study at his or her site, including compliance with the protocol, applicable regulations, and institutional policies. Site-level principal investigators must meet the qualifications set forth in 21 C.F.R. § 312.53 and must be listed on the Form FDA 1572 for their respective sites.
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 because it represents the most clinically meaningful and unambiguous measure of treatment benefit in oncology, is not subject to assessment bias, and is the endpoint typically required by regulatory authorities for approval of new therapies in advanced hepatocellular carcinoma.
10.2 Key Secondary Endpoints
The key secondary endpoints of the CLARION trial are as follows:
Progression-Free Survival (PFS): Defined as the time from the date of randomization to the date of first documented radiographic disease progression per RECIST v1.1 (as assessed by investigator) or death from any cause, whichever occurs first. Subjects who have not experienced disease progression or death at the time of the analysis data cutoff will be censored at the date of their last adequate tumor assessment.
Objective Response Rate (ORR): Defined as the proportion of randomized subjects who achieve a confirmed complete response (CR) or confirmed partial response (PR) as their best overall response, per RECIST v1.1. Confirmation of response requires a repeat tumor assessment performed at least four (4) weeks after the initial response assessment.
Duration of Response (DOR): Defined as the time from the date of first documented objective response (CR or PR) to the date of first documented radiographic disease progression per RECIST v1.1 or death from any cause, whichever occurs first. This endpoint will be analyzed in the subgroup of subjects who achieve a confirmed objective response.
10.3 Safety Endpoints
Safety endpoints for the CLARION trial include the following:
• Incidence, severity (graded per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], current version), and causality assessment of adverse events (AEs) and serious adverse events (SAEs).
• Incidence and severity of clinically significant laboratory abnormalities, including hematology parameters, serum chemistry parameters, and liver function tests.
• Incidence and reasons for dose modifications (dose reductions and dose interruptions) and treatment discontinuations due to adverse events.
• Deaths occurring on study (defined as deaths occurring during the treatment period or within thirty [30] days of the last dose of study treatment), including cause of death.
10.4 Exploratory Endpoints
Exploratory endpoints for the CLARION trial include the following:
• Biomarker analyses, including analyses of tumor tissue samples (archival or fresh biopsy) and circulating biomarkers (e.g., circulating tumor DNA, serum protein markers), to identify potential predictive and prognostic biomarkers of response to penterafenib.
• Patient-reported outcomes (PROs), assessed using validated instruments administered at baseline and at protocol-specified intervals throughout the study, to evaluate the impact of treatment on patient-reported symptoms, functional status, and health-related quality of life.
• Pharmacokinetic (PK) parameters, including plasma concentration-time profiles of penterafenib and its primary metabolites, analyzed centrally by Northbridge Bioanalytical Laboratories, Inc., located at 2900 Commerce Way, Baltimore, Maryland 21224.
• Pharmacodynamic (PD) parameters, including assessments of target modulation and downstream pathway activity, to inform the relationship between drug exposure, pharmacodynamic effects, and clinical outcomes.
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 (42) months, commencing with the first patient enrolled and continuing until the last patient is enrolled. During this period, eligible subjects will be screened, enrolled, and randomized across all participating sites.
• Follow-up Period: Approximately eighteen (18) months following the enrollment of the last patient. During this period, subjects will continue to receive study treatment (if still on treatment), undergo protocol-specified assessments, and be followed for survival.
Key Projected Milestones:
MCTA Enrollment Period Coverage: The MCTA between Penterra and Veridian provides for an enrollment period of forty-two (42) months commencing from the date of the first patient enrolled at any Veridian Network site. Financial provisions under the MCTA, including per-patient site fees, annual site maintenance fees, and network coordination fees, extend through study completion as described in Exhibit B to the MCTA and as summarized in Section 24 of this Protocol Synopsis.
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 discontinuation), and instructions regarding administration with or without food are set forth in the full protocol.
Treatment with penterafenib will continue until the occurrence of any of the following events, whichever occurs first:
• Documented radiographic disease progression per RECIST v1.1, unless the investigator determines, in consultation with the sponsor's medical monitor, that the subject continues to derive clinical benefit from continued treatment;
• Unacceptable toxicity, defined as an adverse event that, in the judgment of the investigator, precludes further treatment with penterafenib despite appropriate dose modification and supportive care;
• Withdrawal of informed consent by the subject;
• Decision by the investigator that discontinuation is in the best interest of the subject; or
• Sponsor decision to terminate the study.
12.2 Control / Comparator
Subjects randomized to the control arm will receive matching placebo oral film-coated tablets. The placebo tablets are identical in appearance (size, shape, color, coating, and weight) to the active penterafenib tablets in order to maintain the integrity of the double-blind design. Placebo tablets contain no active pharmaceutical ingredient. The placebo will be administered on the same dosing schedule as the investigational product, and subjects in the placebo arm will undergo the same assessments and follow the same visit schedule as subjects in the treatment arm.
12.3 Concomitant Therapies
Permitted and prohibited concomitant medications will be specified in the full protocol. In general, all subjects will be permitted to receive best supportive care per institutional standards, including analgesics, anti-emetics, nutritional support, and other symptomatic treatments as clinically indicated. Specific classes of medications that are anticipated to be prohibited due to potential pharmacokinetic interactions or confounding effects on study endpoints will be identified in the full protocol and communicated to investigators during site initiation. Investigators are required to document all concomitant medications in the electronic case report form (eCRF) throughout the study.
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 assessment must be performed within twenty-eight (28) days prior to randomization as part of the screening procedures.
• First 24 Weeks: Tumor assessments will be performed every six (6) weeks (± seven [7] days) from the date of randomization for the first twenty-four (24) weeks.
• After Week 24: Tumor assessments will be performed every nine (9) weeks (± seven [7] days) from Week 24 until documented radiographic disease progression per RECIST v1.1, withdrawal of consent, or study closure, whichever occurs first.
Survival follow-up will be conducted every twelve (12) weeks after treatment discontinuation for subjects who discontinue study treatment prior to death. Survival follow-up may be performed by telephone contact, clinic visit, or review of public records, as specified in the full protocol, and will continue until death, withdrawal of consent for further follow-up, or study closure.
13.2 Safety Assessments
Safety assessments will be conducted throughout the study and will include the following:
• Adverse Event Monitoring: Continuous monitoring and documentation of all adverse events (AEs) from the time of informed consent through thirty (30) days following the last dose of study treatment (or until resolution or stabilization, whichever is later). Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), current version, and assessed for causality (relationship to study treatment) by the investigator.
• Physical Examinations: Complete physical examinations at screening, Day 1 (randomization), and at protocol-specified intervals thereafter. Abbreviated, symptom-directed physical examinations may be performed at intervening visits as clinically indicated.
• Vital Signs: Assessment of blood pressure, heart rate, body temperature, respiratory rate, and weight at each study visit.
• ECOG Performance Status: Assessed at screening, Day 1, and at each scheduled study visit.
• Laboratory Assessments: Hematology (complete blood count with differential), serum chemistry (including electrolytes, renal function, and hepatic function panels), liver function tests (ALT, AST, alkaline phosphatase, total bilirubin, albumin), coagulation parameters (INR, aPTT), and urinalysis will be performed at screening, Day 1, and at protocol-specified intervals throughout the study. Additional unscheduled laboratory assessments may be performed as clinically indicated.
• Electrocardiograms (ECGs): Twelve-lead electrocardiograms will be performed at screening, Day 1, and at protocol-specified intervals during the treatment period. ECGs will be assessed locally by the investigator, and centralized ECG analysis may be performed as specified in the full protocol.
13.3 Pharmacokinetic and Biomarker Assessments
Pharmacokinetic Assessments: Blood samples for pharmacokinetic (PK) analysis will be collected at protocol-specified timepoints during the study. All PK samples will be processed, stored, and shipped in accordance with the laboratory manual provided by Northbridge Bioanalytical Laboratories, Inc., and will be analyzed centrally at the Northbridge facility located at 2900 Commerce Way, Baltimore, Maryland 21224. PK parameters to be determined include, but are not limited to, peak plasma concentration (Cmax), time to peak concentration (Tmax), area under the plasma concentration-time curve (AUC), and trough concentrations at steady state.
Biomarker Assessments: Tumor tissue samples (archival formalin-fixed paraffin-embedded [FFPE] blocks or freshly obtained biopsy specimens) will be collected from all subjects, where available, for biomarker analyses. The specific biomarker assays to be performed will be described in the full protocol and the biomarker analysis plan. Circulating biomarker blood samples (including samples for circulating tumor DNA [ctDNA] analysis) will be collected at baseline and at protocol-specified intervals during the study.
13.4 Patient-Reported Outcomes
Patient-reported outcome (PRO) assessments will be administered using validated instruments at baseline (prior to randomization) and at protocol-specified intervals throughout the treatment and follow-up periods. The specific PRO instruments to be used will be identified in the full protocol and may include measures of symptom burden, functional status, and global health-related quality of life. PRO data will be collected electronically, where feasible, using electronic patient-reported outcome (ePRO) devices or through the EDC system.
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 triggered upon the occurrence of the corresponding study visit or assessment event as documented in the electronic data capture (EDC) system and verified by the site and the CRO monitor.
The End-of-Treatment Visit must be completed within thirty (30) days of the last dose of study treatment for each subject. Survival follow-up visits will continue every twelve (12) weeks following treatment discontinuation until death, withdrawal of consent for further follow-up, or closure of the study by the sponsor, whichever occurs first. The costs associated with the End-of-Treatment Visit and survival follow-up are encompassed within the four milestone payments described above.
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.
Data Entry: All clinical data collected during the CLARION trial will be entered by authorized site personnel into the validated EDC system using electronic case report forms (eCRFs) designed specifically for this protocol. Data entry must be performed by qualified and trained site personnel who have been granted user access to the EDC system. Training on the use of the EDC system will be provided to all authorized site personnel prior to the initiation of data entry at each site.
Data Management and Quality Review: Clinical data management, including data review, query generation and resolution, medical coding (MedDRA for adverse events; WHO Drug Dictionary for concomitant medications), and database lock procedures, will be performed by the data management group at Meridian CRO in accordance with the data management plan for the study and applicable standard operating procedures.
Compliance with 21 C.F.R. Part 11: The EDC system used in this study complies with the requirements of 21 C.F.R. Part 11 (Electronic Records; Electronic Signatures), including requirements for system validation, audit trails, electronic signatures, record retention, and access controls. All electronic records generated in the EDC system will be maintained in compliance with Part 11 throughout the study and for the required retention period thereafter.
Source Document Verification: Source document verification ("SDV") will be performed by Meridian CRO clinical monitors during on-site monitoring visits to confirm that data entered in the eCRFs are accurate, complete, and consistent with the source documents maintained at the site. The extent and frequency of SDV will be specified in the monitoring plan for the study.
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 hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, or is an important medical event that may jeopardize the subject or require intervention to prevent one of the foregoing outcomes, as defined in 21 C.F.R. § 312.32. SAE reports must be submitted using the sponsor-designated SAE reporting forms and procedures, as detailed in the study-specific safety reporting manual provided to each site.
IND Safety Reports (Sponsor Obligation): As the IND holder, Penterra is responsible for the submission of IND safety reports to the FDA in accordance with 21 C.F.R. § 312.32, including:
• 7-Day Reports: For any adverse event that is both serious and unexpected and is associated with the use of the investigational product, and that is fatal or life-threatening, Penterra will submit an IND safety report to the FDA as soon as possible but in no event later than seven (7) calendar days after initial receipt of the information.
• 15-Day Reports: For all other serious, unexpected suspected adverse reactions associated with the use of the investigational product, Penterra will submit an IND safety report to the FDA as soon as possible but in no event later than fifteen (15) calendar days after initial receipt of the information.
Safety Oversight: Safety oversight for the CLARION trial is coordinated among the following entities:
• Penterra Pharmaceuticals Corp.: Dr. Elaine Whitford, M.D., Chief Medical Officer, serves as the sponsor's medical monitor for the study and is responsible for ongoing medical review of safety data, assessment of individual safety reports, and communication of safety-related information to investigators, regulatory authorities, and the DSMB.
• Meridian CRO: Meridian CRO's pharmacovigilance and safety reporting group is responsible for the day-to-day processing, quality review, and regulatory reporting of safety data, including SAE processing, signal detection, and preparation of aggregate safety reports.
• Independent Data Safety Monitoring Board (DSMB): An independent DSMB will be constituted for the CLARION trial pursuant to a separate DSMB charter. The DSMB will be composed of independent physicians, biostatisticians, and other experts with no financial or other conflicts of interest with respect to the sponsor or the investigational product. The DSMB will be responsible for periodic review of unblinded safety data, conduct of pre-specified interim efficacy and futility analyses, and provision of recommendations to the sponsor regarding the continuation, modification, or termination of the study based on the accumulated safety and efficacy data.
Detailed Safety Reporting Procedures: Detailed procedures for safety reporting, including SAE reporting forms, reporting timelines, follow-up procedures, and communication protocols, are set forth in Exhibit J to the MCTA.
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 specific assumptions underlying the sample size calculation, including the assumed median overall survival in the placebo arm, the targeted hazard ratio, the type I error rate, and the planned number of events required for the primary analysis, are detailed in the full protocol and the statistical analysis plan. The sample size is designed to account for anticipated dropout rates and the planned interim analysis.
Primary Analysis: The primary analysis of overall survival will be performed using a log-rank test stratified by the pre-specified stratification factors. A Cox proportional hazards regression model, stratified by the same factors, will be used to estimate the hazard ratio and its associated 95% confidence interval. Kaplan-Meier methodology will be used to estimate the median overall survival and survival rates at clinically relevant timepoints in each treatment arm.
Alpha Level: The primary analysis will be conducted at a two-sided significance level of α = 0.05. The overall type I error rate will be controlled at 0.05 after adjustment for the planned interim analysis, using a pre-specified alpha-spending function (the specific method, such as the O'Brien-Fleming or Lan-DeMets approach, will be detailed in the statistical analysis plan).
Interim Analyses: At least one formal interim analysis is planned for the CLARION trial, to be conducted by the independent DSMB after a pre-specified number of overall survival events have been observed. The interim analysis will include assessments of both efficacy (to determine whether early evidence of a treatment benefit warrants consideration of early termination for efficacy) and futility (to determine whether the accumulated data suggest that the trial is unlikely to demonstrate a statistically significant benefit upon completion of enrollment). The specific timing, stopping boundaries, and decision rules for the interim analysis will be set forth in the DSMB charter and the statistical analysis plan.
Biostatistical Analysis: All biostatistical analyses for the CLARION trial, including the primary, secondary, exploratory, and safety analyses, will be performed by the biostatistics group at Meridian CRO in accordance with the statistical analysis plan approved by the sponsor. The statistical analysis plan will be finalized and approved prior to database lock.
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 holder, is responsible for compliance with all provisions of Part 312, including IND submission and maintenance, protocol compliance, investigator selection and oversight, safety reporting, and recordkeeping.
• 21 C.F.R. Part 50 — Protection of Human Subjects. All aspects of the study involving human subjects, including the informed consent process, will comply with the requirements of Part 50.