Overview
Arm 1 ( Phase 2/3 Run in ):
PRV111: Topical Locoregional Delivery Placed Over the Tumor Region Primary Endpoint: Overall Response Rate (ORR) Primary Objective: Demonstrate the safety and efficacy of PRV111 in patients with Carcinoma in Situ (CIS) (WHO 2017)
Arm 2 (Phase 1) PRV211: Intraoperative Locoregional Delivery Placed into the Resected Tumor Bed Primary Endpoint: Safety Primary Objective: Determine Safety of PRV211 in intraoperative setting
Arm 3 (Phase 1/2) PRV131: Intratumoral Injectable delivery into the Tumor Primary Endpoint: Safety and Objective Response Rate (ORR) Primary objective: Determine a safe and effective dose for PRV131 intratumoral injectable
Subject Assignment: Subjects will be assigned to Arm 1, Arm 2, or Arm 3 of this study based on disease staging Arm 1: Pathologically proven and clinically confirmed Tis/CIS of the lip or oral cavity Arm 2: Pathologically proven and clinically confirmed T1-T3, Nx, M0 of the lip or oral cavity Arm 3a: Histologically confirmed squamous cell carcinoma (SCC) of the oral cavity, classified as clinical stage T1-T3, N0-1, M0 Arm 3b: Histologically confirmed malignant tumor in the lungs (primary or secondary), classified as clinical stage T1-2, N0, M0
Description
Privo's PRV111 \& PRV211 \& PRV131 Product Description:
PRV111 (Cisplatin Transmucosal System) is a thin, 2-layer, matrix-type, transmucosal patch consisting of a chitosan matrix layer embedded with cisplatin loaded chitosan particles (CLPs) and a non-woven fabric adhesive unidirectional backing, which is applied to the matrix layer during manufacturing. The patch is self-adhesive.
In addition to the PRV111 patch, a separately packaged Permeation Enhancer (PE) Powder for Reconstitution is used in conjunction with PRV111. The reconstituted PE Solution is intended to improve the absorption of the cisplatin active ingredient and will be applied prior to patch application.
PRV211 is a nanoengineered delivery system intended for intraoperative chemotherapy treatment for all solid tumor surgeries immediately following surgical excision. The goal is to treat the tumor bed locally, eliminating any remaining micrometastases or close margins that are unable to be fully resected while avoiding system circulation.
PRV131 is a nanoparticle-based cisplatin formulation designed for intratumoral administration. The product is reconstituted with a separately packaged diluent to form a suspension for injection. Upon intratumoral administration, the nanoparticles facilitate deep tumor penetration and localized drug release, enabling high local drug concentrations while minimizing systemic exposure.
ARM 1 Study Details PRV111 Topical Treatment
Screening: A screening period of up to 7 days is needed to evaluate subject eligibility for study participation. All subjects will undergo a baseline histopathological assessment at screening (confirming CIS of the oral cavity for inclusion), if an existing diagnosis does not exist. Also at screening, the investigator will determine if the patient requires surgery, and will assess the rest of the inclusion/exclusion criteria to check for eligibility.
Dose limiting Toxicity (DLT): DLT is defined as a clinically significant treatment-emergent AE (TEAE) or laboratory abnormality unrelated to surgery and/or disease progression, concurrent illness, or concomitant therapy within 1-month post-surgery Note: The dosing of 1.5 mg/cm2 per visit in this protocol is comparable to the one used in the prior completed phase 1/2 CLN-001 study, which has shown safety and efficacy causing no dose limiting toxicities (DLTs), related severe adverse events (SAEs) or systemic side effects.
Photo documentation: Tumors will be photographed including anatomic landmarks at each visit, prior to treatment at treatment visits for the ability to compare between visits. Photos are also required for documenting the location of biopsies taken. Additional details are provided in the Lab Manual.
Minimum Required Treatments for Efficacy Assessment: For assessing efficacy, each subject must complete at least 3 treatment visits.
Assessment for Postponement of Surgery: Response Assessment Criteria: If disease is not improved compared to baseline biopsy, subject proceeds to scheduled surgery, otherwise the subject will continue on with the PRV111 treatment regimen.
ARM 2 Study Details PRV211 Intraoperative Treatment
Screening: A screening period of up to 7 days is needed to evaluate subject eligibility for study participation. All subjects will be screened based on the SOC biopsy to obtain baseline histopathology. This biopsy will confirm the stage of the disease to be T1-T3, Nx, M0 of the oral cavity, amenable to surgery. Based on this confirmation, the rest of the inclusion/exclusion criteria will be checked for eligibility.
Safety and Efficacy of PRV211 Treatment: The safety of PRV211 treatment will be determined in the Safety Run-in study described below. Once the safety is determined, a second expansion study can be initiated in another study. The efficacy of PRV211 is determined in the expansion study. This efficacy will be assessed by the incidence of locoregional recurrence at 12 months.
Initial Safety Lead-in Study: This is an open label, safety lead-in phase 1b dose confirmation study in patients with T1-T3, Nx, M0 oral cancer, followed by an expansion phase 2 single arm study as an intraoperative chemotherapy with PRV211. For the purpose of safety detection, if greater than 33% of subjects being evaluated for safety present with dose-limiting toxicities (DLTs), the study is deemed unsafe.
For the Safety Lead-in Study, 3 subjects will be initially enrolled. If more than 1 subject has dose limiting toxicity (DLT), the study stops. Otherwise, 3 additional subjects will be enrolled and if more than 2 DLTs are detected in the total of 6 subjects, the study is deemed unsafe and the study stops. If 2 or less DLTs are observed, the treatment will be considered safe.
At the conclusion of the Safety Lead-in portion (6 patients), if PRV211 is determined to be safe, an expansion study can be initiated. The 6 subjects from the Safety Lead-in study will be included in the expansion study and these patients will be monitored for efficacy.
ARM 3 Study Details PRV131 Intratumoral Injectable
Screening: A screening period of up to 7 days is needed to evaluate subject eligibility for study participation. All subjects will undergo baseline histopathological confirmation prior to enrollment. For subjects assigned to Arm 3a, disease must be confirmed as squamous cell carcinoma (SCC) of the oral cavity, classified as T1-T3, N0-1, M0. For subjects assigned to Arm 3b, disease must be confirmed as a malignant tumor in the lungs (primary or secondary), classified as T1-T2, N0, M0. Baseline imaging and clinical assessments will be performed per standard of care (SOC) to confirm tumor accessibility for intratumoral injection and surgical eligibility.
Safety and Efficacy of PRV131 Treatment: The safety and preliminary efficacy of PRV131 will be evaluated in a Phase 1/2 run-in study designed to determine a safe and effective dose for intratumoral administration. Safety will be assessed based on the incidence of dose-limiting toxicities (DLTs), adverse events, and clinical laboratory findings. Efficacy will be evaluated based on Objective Response Rate (ORR), as determined by clinical, radiologic, and histopathological assessment of tumor response following treatment.
Dose Escalation and Optimization: This is an open-label, dose escalation and dose optimization study utilizing a standard 3+3 design. Three subjects will initially be enrolled in the medium dose cohort. If no DLTs are observed, dose escalation will proceed. If one DLT is observed, the cohort will be expanded to 6 subjects. If two or more DLTs are observed at any dose level, escalation will be halted and the prior dose level may be considered the maximum tolerated dose (MTD). If one or fewer DLTs are observed among 6 subjects, escalation may continue. Following dose escalation, additional subjects may be enrolled in a dose optimization phase to further evaluate safety, tolerability, pharmacokinetics, and preliminary efficacy.
Treatment Administration: Treatment is customized based on tumor size and delivered directly into the tumor to maximize local drug concentration while minimizing systemic exposure. Subjects in Arm 3a will receive 2 to 3 intratumoral injections approximately 1 to 2 weeks apart prior to surgical resection. Subjects in Arm 3b will receive a single intratumoral injection, which may be administered during diagnostic bronchoscopy or at a subsequent visit following confirmation of malignancy. Surgical resection will occur approximately 2 to 4 weeks following treatment.
Post-Treatment and Surgical Assessment: All subjects will proceed to standard-of-care surgical resection following PRV131 treatment. Resected tumor tissue will undergo histopathological evaluation to assess treatment response. Imaging and clinical findings will be compared with histopathological outcomes to evaluate the consistency and predictability of treatment effect. Subjects will be followed per SOC to monitor safety, recurrence, and durability of response.
Eligibility
Different diagnosis for ARM 1 \& ARM 2, however the rest of inclusion criteria are the same for both arms:
In order to be eligible to participate in the study, an individual must meet all of the following criteria:
• Diagnosis Arm 1: Pathologically proven and clinically confirmed Tis/CIS of the lip or oral cavity Arm 2: Pathologically proven and clinically confirmed T1-T3, Nx,M0 of the lip or oral cavity
Criteria for Inclusion for both ARM 1 \& ARM 2:
- Tumors for which the cytological and architectural changes upon histopathological assessment warrant surgical intervention
- Adult subjects, men and women, defined by age ≥18 years at the time of screening.
- Tumor must be accessible, with no evidence of infection or active bleeding.
- Tumor is amenable to surgical resection within 8 weeks of screening visit (Visit 0).
- Clinically and/or radiologically measurable tumor.
- Eastern Collaborative Oncology Group Performance Status of ≤2.
- Male and female subjects of childbearing potential must agree to use 2 methods of effective contraception from screening and for at least 30 days after the final dose of investigational product. Appropriate birth control is defined as barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices, or naturally or surgically sterile (with documentation in the subject's medical records). Postmenopausal women are defined as presenting at least 12 months' natural spontaneous amenorrhea, or at least 6 weeks following surgical menopause (bilateral oophorectomy). Females of childbearing potential must be non-lactating and have a negative serum hCG within 14 days of treatment initiation.
- Absence of any serious underlying medical conditions which could impair the ability of the subject to participate in the study.
- Have a life expectancy of ≥3 months.
- Willing and able to provide written informed consent.
- Able to return to study site for treatment and follow-up visits as defined in the Protocol.
Criteria for Exclusion for both ARM 1 and ARM 2 (unless specified):
An individual who meets any of the following criteria will be excluded from participation in the study:
- Subjects that are not eligible for surgery as SOC.
- Patients with a prior history of invasive squamous cell carcinoma (Arm 1 only)
- Tumors involving the marginal gingiva (Arm 1 only)
- Squamous cell carcinoma (SCC) of the oral cavity that received previous radiotherapy.(Arm 1 only)
- Systemic chemotherapy for the treatment of SCC of the head and neck less than 2 years prior to Screening (Arm 1 only)
- Concurrent documented malignancy, with the exception of localized SCCs and basal cell carcinoma of the skin Exposure to any investigational agent within 3 months prior to Screening
- Known allergy or hypersensitivity to platinum-containing agents, or known intolerance to a prior platinum- containing agent, or to any of the excipients, which, in the judgement of the physician will preclude re- exposure to platinum-containing agent
- Active, uncontrolled infection requiring systemic therapy, such as but not limited to HIV, Syphilis, Hepatitis B, or Hepatitis C
- Uncontrolled intercurrent illness that would risk subject safety, interfere with the objectives of the Protocol, or limit subject compliance with study requirements, as determined by the Investigator
- Known or suspected pregnancy, planned pregnancy, or lactation
- Any medical or psychiatric condition that may compromise the ability to give written informed consent
- Known diagnosis of oral submucous fibrosis (Arm 1 only)
- Known diagnosis of trismus (Arm 1 only)
Arm 3a:
Inclusion Criteria
Participants must meet all the following criteria to be eligible for the study:
- Age: 18 years or older at the time of screening.
- Diagnosis: Histologically confirmed squamous cell carcinoma (SCC) of the oral cavity, classified as clinical stage T1-T3, N0-N1, M0. This includes SCC of the lip with a significant mucosal component.
- Tumor Accessibility: Tumor must be accessible for intratumoral injection, with no evidence of active infection.
- Measurable Disease: Presence of clinically and/or radiologically measurable tumor.
- Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
- Life Expectancy: Estimated life expectancy of at least 3 months.
- Informed Consent: Ability and willingness to provide written informed consent.
- Compliance: Ability to return to the study site for treatment visits as defined in the protocol.
- Contraception: For participants of childbearing potential, agreement to use two effective methods of contraception during the study period.
Exclusion Criteria
Participants meeting any of the following criteria will be excluded from the study:
- Surgical Eligibility: Not eligible for standard-of-care (SOC) surgery.
- Renal and Hepatic Function: Abnormal renal and hepatic functions as determined by the investigator.
- Cardiac Function: Corrected QT interval (QTc) \> 470 ms for women and \> 450 ms for men.
- Bone Involvement: Known bone involvement by the tumor (Stage T4).
- Other Cancers: Diagnosis of salivary gland cancer.
- Prior Treatments: History of oral cancers that were nonresponsive to radiation or platinum-based chemotherapy within the past 12 months.
- Multifocal Disease: Presence of multifocal invasive oral squamous cell carcinoma (OSCC).
- Investigational Agents: Exposure to any investigational agent within 3 months prior to screening.
- Allergies: Known allergy or hypersensitivity to platinum-containing agents or any excipients in the study drug, or known intolerance to prior platinum-based therapy that would preclude re-exposure.
- Infections: Active, uncontrolled infections requiring systemic therapy, including but not limited to HIV, syphilis, hepatitis B, or hepatitis C.
- Comorbid Conditions: Uncontrolled intercurrent illness that would pose a risk to subject safety, interfere with study objectives, or limit compliance, as determined by the investigator.
- Pregnancy and Lactation: Known or suspected pregnancy, planned pregnancy, or current lactation.
- Consent Capacity: Any medical or psychiatric condition that may compromise the ability to provide written informed consent.
3b: Inclusion Criteria
Participants must meet all the following criteria to be eligible for the study:
- Age: 18 years or older at the time of screening.
- Diagnosis: Histologically confirmed malignant tumor in the lungs (primary or secondary), classified as clinical stage T1-T2, N0, M0.
- Tumor Accessibility: Tumor must be accessible for intratumoral injections via a bronchoscope, with no evidence of active infection.
- Measurable Disease: Presence of clinically and/or radiologically measurable tumor.
- Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
- Life Expectancy: Estimated life expectancy of at least 3 months.
- Informed Consent: Ability and willingness to provide written informed consent.
- Compliance: Ability to return to the study site for treatment visits as defined in the protocol.
- Contraception: For participants of childbearing potential, agreement to use two effective methods of contraception during the study period.
Exclusion Criteria
Participants meeting any of the following criteria will be excluded from the study:
- Surgical Eligibility: Not eligible for standard-of-care (SOC) surgery.
- Renal and Hepatic Function: Abnormal renal and hepatic functions as determined by the investigator.
- Cardiac Function: Corrected QT interval (QTc) \> 470 ms for women and \> 450 ms for men.
- Bone Involvement: Known bone involvement by the tumor (Stage T4).
- Other Cancers: Active concurrent malignancies that require systemic therapy.
- Prior Treatments: History of cancers in the lung that were nonresponsive to radiation or platinum-based chemotherapy within the past 12 months.
- Investigational Agents: Exposure to any investigational agent within 3 months prior to screening.
- Allergies: Known allergy or hypersensitivity to platinum-containing agents or any excipients in the study drug or known intolerance to prior platinum-based therapy that would preclude re-exposure.
- Infections: Active, uncontrolled infections requiring systemic therapy, including but not limited to HIV, syphilis, hepatitis B, or hepatitis C.
- Comorbid Conditions: Uncontrolled intercurrent illness that would pose a risk to subject safety, interfere with study objectives, or limit compliance, as determined by the investigator.
- Pregnancy and Lactation: Known or suspected pregnancy, planned pregnancy, or current lactation.
- Consent Capacity: Any medical or psychiatric condition that may compromise the ability to provide written informed consent.
