Reqorsa (Quaratusugene Ozeplasmid) in Combination With Pembrolizumab in Previously Treated Non-Small Lung Cancer (Acclaim-2)

• ClinicalTrials.gov Identifier: NCT05062980
• Recruitment Status: Recruiting
• First Posted: September 30, 2021
• Last Update Posted: September 13, 2022
• Sponsor: Genprex, Inc.
• Information provided by (Responsible Party): Genprex, Inc.

Study Description

Brief Summary:

The purpose of this randomized study is to determine the safety and efficacy of Reqorsa (quaratusugene ozeplasmid, formerly known as GPX-001), in combination with pembrolizumab in patients with previously treated NSCLC. Reqorsa consists of non-viral lipid nanoparticles that encapsulate a DNA plasmid with the TUSC2 tumor suppressor gene, and is the first systemic gene therapy.

The study will be conducted in 2 phases, a dose escalation and expansion phase (Phase 1) and a safety and efficacy evaluation phase (Phase 2). In Phase 1, patients will be enrolled in sequential cohorts treated with successively higher doses of Reqorsa in combination with pembrolizumab. When the recommended Phase 2 dose (RP2D) is determined, additional patients will be enrolled in an expansion cohort.

In Phase 2, patients will be randomized to receive Reqorsa with pembrolizumab or docetaxel +/- ramucirumab (active comparator).

Condition or disease	Intervention/treatment	Phase
Non Small Cell Lung Cancer	Biological: quaratusugene ozeplasmid; Drug: pembrolizumab; Drug: docetaxel; Drug: ramucirumab	Phase 1; Phase 2

Detailed Description:

Acclaim-2 is a multi-center, open-label 2-arm study of Reqorsa in combination with pembrolizumab versus docetaxel +/- ramucirumab (active comparator) in previously treated NSCLC with any PD-L1 TPS and NOT considered refractory to pembrolizumab, as defined by having achieved at least a 3-month clinical benefit to previous pembrolizumab-containing treatment.

The total duration of study for each patient will be dependent upon the safety, tolerability, and efficacy of the study treatment.

The Phase 1 portion of the study will involve a 3+3 dose escalation schema of Reqorsa up to 0.12 mg/kg in combination with a fixed dose of pembrolizumab (200 mg) administered once via intravenous (IV) infusion during each 21-day treatment cycle. Three Reqorsa doses will be tested (0.06, 0.09 and 0.12 mg/kg administered on Day 1 of a 21-day treatment cycle). Once the RP2D is identified an expansion cohort will be enrolled to better characterize safety, tolerability, and preliminary anti-tumor activity.

The Phase 2 portion of the study is a randomized, open-label 2-arm study of Reqorsa in combination with pembrolizumab versus docetaxel ± ramucirumab. In Phase 2, 126 patients will be randomized 2:1 to the investigational versus comparator treatment arms, respectively. Patients will be stratified by NSCLC histology (squamous [SQ] versus nonsquamous [NSQ]) predominant histology for efficacy analysis purposes. The 84 patients randomized to the combination arm will receive Reqorsa, at the RP2D identified in Phase 1, in combination with 200 mg pembrolizumab either during each 21- day cycle until disease progression or unacceptable toxicity as determined by the investigator. The 42 patients randomized to the active comparator arm will receive docetaxel at the FDA- approved dose of 75 mg/m2 every 21 days until disease progression or unacceptable toxicity as determined by the investigator. Investigators are permitted to administer docetaxel in combination with ramucirumab at their discretion.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Phase 1: 3+3 dose escalation to identify RP2D followed by a 12 patient dose expansion cohort. Phase 2: Parallel randomization in a 2:1 ratio to either Reqorsa at RP2D in combination with pembrolizumab or docetaxel +/- ramucirumab.
• Masking: Single (Outcomes Assessor)
• Masking Description: Tumor responses will be assessed centrally using RECIST 1.1 criteria by an independent radiology group blinded to treatment arm assignment.
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Open-Label, Dose-Escalation and Clinical Response Study of Quaratusugene Ozeplasmid in Combination With Pembrolizumab Versus Docetaxel With or Without Ramucirumab in Patients With Previously Treated Non-Small Cell Lung Cancer
• Actual Study Start Date: March 30, 2022
• Estimated Primary Completion Date: May 2025
• Estimated Study Completion Date: May 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1; Up to 3 sequential dose escalation cohorts will be treated with Reqorsa intravenously on Day 1 in addition to pembrolizumab 200 mg fixed dose infusion every 21 days until progression or unacceptable toxicity. The first group will receive Reqorsa IV infusion at 0.06 mg/kg, the next group 0.09 mg/kg and the third group will receive 0.12 mg/kg. Once the RP2D is determined, an additional group of patients will be enrolled at the RP2D.	Biological: quaratusugene ozeplasmid; Quaratusugene ozeplasmid is an experimental non-viral immunoogene therapy utilizing the TUSC2 gene, designed to target cancer cells by interrupting cell signaling pathways that allow cancer cells to grow, re-establishing pathways that promote cancer cell death and modulating the immune system response against cancer cells.; Other Names: GPX-001; Reqorsa; Drug: pembrolizumab; Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody indicated for treatment of patients with metastatic NSCLC.; Other Name: Keytruda
Experimental: Phase 2 Combination; Patients will receive the RP2D of Reqorsa intravenously on Day 1 in addition to pembrolizumab 200 mg fixed dose infusion every 21 days until progression or unacceptable toxicity.	Biological: quaratusugene ozeplasmid; Quaratusugene ozeplasmid is an experimental non-viral immunoogene therapy utilizing the TUSC2 gene, designed to target cancer cells by interrupting cell signaling pathways that allow cancer cells to grow, re-establishing pathways that promote cancer cell death and modulating the immune system response against cancer cells.; Other Names: GPX-001; Reqorsa; Drug: pembrolizumab; Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody indicated for treatment of patients with metastatic NSCLC.; Other Name: Keytruda
Active Comparator: Phase 2; Patients will receive docetaxel 75 mg/m2 infusion with or without ramucirumab 10 mg/kg infusion every 21 days until progression or unacceptable toxicity.	Drug: docetaxel; Docetaxel is a microtubule inhibitor indicated for locally advanced or metastatic NSCLC after platinum-based chemotherapy failure.; Drug: ramucirumab; Ramucirumab is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist indicated for in combination with docetaxel for treatment of NSCLC with disease progression after platinum-based chemotherapy.; Other Name: Cyramza

Outcome Measures

Primary Outcome Measures :

1. Recommended Phase 2 Dose (RP2D) - Phase 1 [ Time Frame: First 21-days at each dose level ]

   RP2D which will be the MTD or if the MTD is not defined by the safety data, the RP2D will be determined based on an integrated assessment of all available clinical safety and preliminary efficacy data.

   The number of participants with dose-limiting toxicity (DLT) events utilizing 3+3 dose escalation design will be used to identify the MTD. Dose may be escalated or de-escalated based on the occurrence of DLTs to identify the MTD. All events will be assessed by the Investigator for possible, probable or definite relation to either drug administered.

2. Progression-free Survival (PFS) - Phase 2 [ Time Frame: Approximately 8 months ]
   Number of months from randomization to the date of disease progression, confirmed by RECIST v1.1 criteria or to the date of death due to any cause.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adults ≥ 18 years of age.
2. Voluntarily signed an informed consent in accordance with institutional policies.
3. Histologically or cytologically documented NSCLC with locally advanced or metastatic disease. Note: Any level of PD-L1 TPS is allowed.
4. Achieved clinical benefit to prior pembrolizumab or pembrolizumab/platinum-based chemotherapy for at least 3 months and subsequently progressed as confirmed by radiological tumor assessment. Patients receiving pembrolizumab as a single agent must have additional therapy with a platinum-based chemotherapy prior to enrolling, but patients receiving pembrolizumab/platinum-based chemotherapy should have enrollment in this trial as the next treatment regimen.
5. Patients with genetic alterations with FDA-approved therapy (such as EGFR or anaplastic lymphoma kinase [ALK] mutations) must have disease progression after treatment with appropriate targeted therapy and must be eligible for immunotherapy as determined by the investigator.
6. Eastern Cooperative Oncology Arm (ECOG) performance score from 0 to 1.
7. Must be ≥ 28 days beyond major surgical procedures such as thoracotomy, laparotomy, or joint replacement, and must be ≥ 10 days beyond minor surgical procedures such as biopsy of subcutaneous tumors, pleuroscopy, etc., and must not have evidence of wound dehiscence, active wound infection, or comparable major residual complications of the surgery.

8. Demonstrate adequate organ function, as determined by the following laboratory values obtained within 21 days prior to enrollment:

   1. Absolute neutrophil count (ANC) ≥ 1,500/μL,
   2. Platelets ≥ 100,000/μL,
   3. Hemoglobin ≥ 9.0 g/dL ≥ 4 weeks without transfusions,
   4. International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × upper limit of normal (ULN) unless the patient is receiving anticoagulant therapy as long as PT is within therapeutic range of intended use of anticoagulants,
   5. Activated Partial Thromboplastin Time (aPTT) or Partial Thromboplastin Time (PTT): ≤ 1.5 × ULN unless the patient is receiving anticoagulant therapy as long as aPTT is within therapeutic range of intended use of anticoagulants,
   6. Creatinine ≤ 1.5 × ULN OR Calculated creatinine clearance (CrCl) ≥ 60 mL/min for patients with creatinine levels > 1.5 × ULN,
   7. Serum total bilirubin ≤ 1.0 × ULN,
   8. AST and ALT ≤ 1.5 × ULN,
   9. Alkaline phosphatase ≤ 2.5 x ULN.
9. Stable cardiac condition with a left ventricular ejection fraction > 40%.

10. If asymptomatic brain metastases are present, must meet ALL criteria listed (a-d):

    1. No history of seizures in the preceding 6 months,
    2. Definitive treatment must be completed ≥ 4 weeks prior to enrollment,
    3. Stopped steroid treatments administered because of brain metastases or related symptoms for ≥ 2 weeks prior to enrollment,
    4. Post-treatment imaging must demonstrate stability or regression of the brain metastases.
11. Female patients must have a negative serum pregnancy test at screening (within 7 days of enrollment) if of childbearing potential or be of non-childbearing potential.
12. Female patients of childbearing potential and non-sterile male patients with female partner(s) of childbearing potential must agree to use two forms of contraception including one highly effective and one effective method beginning ≥ 2 weeks prior to enrollment through 4 months following the last dose of study treatment.
13. Male patients must agree to no sperm donation during study treatment and for an additional 4 months following the last dose of study treatment.

Exclusion Criteria:

1. Unable to tolerate pembrolizumab treatment, leading to early treatment discontinuation or prolonged/ frequent dosage modifications as determined by the investigator.
2. Hypersensitivity to docetaxel or polysorbate 80 (Phase 2 only)
3. Patients at risk of tumor lysis syndrome [e.g., renal impairment, hyperuricemia, bulky tumor (Phase 2 only)]
4. Received prior systemic chemotherapy or monoclonal antibodies for the treatment of the participant's advanced or metastatic disease within 1 month of study enrollment
5. Received prior gene therapy.
6. Received any radiotherapy to the skull, spine, thorax or pelvis within 1 month of study enrollment.
7. Expected to require any other form of antineoplastic therapy while participating in the study.
8. Received a live-virus vaccination within 1 month of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
9. Has known active CNS metastases and/or carcinomatous meningitis.
10. Active, known, or suspected autoimmune disease.
11. Active systemic viral, bacterial, or fungal infections(s) requiring treatment.
12. Serious concurrent illness or psychological, familial, sociological, geographical, or other condition that, in the opinion of the investigator, would prevent adequate follow-up and compliance with the study protocol.
13. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study enrollment. Inhaled or topical steroids and adrenal replacement doses ≤10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
14. Active concurrent malignancies, i.e., cancers other than NSCLC.
15. Has a second, concurrent, untreated malignancy.
16. History of symptomatic interstitial lung disease or pneumonitis that required oral or IV glucocorticoids to assist with management.
17. History of myocardial infarction or unstable angina within the past 6 months.
18. Presence of pre-existing peripheral neuropathy that is ≥ Grade 2 by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE) criteria.
19. Is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol) requiring medical intervention.
20. Known human immunodeficiency virus (HIV) infection or has active hepatitis infection.
21. Female patients who are pregnant or breastfeeding.

Contacts and Locations

Contacts

Contact: Sr Director, Clinical Operations; 1-877-774-GNPX; kcombs@genprex.com

Contact: Chief Medical Officer; 1-877-774-GNPX; mberger@genprex.com

Locations

United States, Florida

Moffitt Cancer Center - Magnolia Campus; Recruiting

Tampa, Florida, United States, 33612

Contact: Alberto A Chiappori, MD 813-745-4541 Alberto.Chiappori@moffitt.org

Contact: Brittany Gorr 813-745-1654 brittany.gorr@mottitt.org

United States, Missouri

Washington University School of Medicine - Siteman Cancer Center; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Daniel Morgensztern, MD 800-600-3606 Patient_Care_Coordination_Center@bjc.org

Principal Investigator: Daniel Morgensztern, MD

United States, Texas

Millennium Oncology; Recruiting

Houston, Texas, United States, 77090

Contact: John Waldron 877-870-2640 jwaldron@wmrad.com

Principal Investigator: Krishna K. Pachipala, MD

Sponsors and Collaborators

Genprex, Inc.

Investigators

• Principal Investigator: Daniel Morgensztern, MD; Washington University School of Medicine

More Information

• Responsible Party: Genprex, Inc.
• ClinicalTrials.gov Identifier: NCT05062980
• Other Study ID Numbers: ONC-004
• First Posted: September 30, 2021
• Last Update Posted: September 13, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Genprex, Inc.:

Tumor suppressor gene 2 (TUSC2); Lipid nanoparticle (LNP); pembrolizumab; Keytruda; Gene therapy; NSCLC; docetaxel; Reqorsa; Acclaim-2; quaratusugene ozeplasmid

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Docetaxel; Pembrolizumab; Ramucirumab; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological