Phase 1 Study of RBN-2397, an Oral PARP7 Inhibitor, in Patients With Solid Tumors

Study Overview
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Brief Summary
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RBN-2397 inhibits PARP7, an enzyme that is switched on by cancer stresses, such as the toxins in cigarette smoke. Cancer cells use PARP7 to hide from the immune system by stopping the cell from sending a signal (Type 1 interferon) that tells the immune system that something is wrong and to kill the cell. RBN-2397 has been shown in animal studies to inhibit tumor growth and also shuts down the don't kill me signal the tumor is sending to evade the immune system. As a PARP7 inhibitor RBN-2397 is different from drugs inhibiting PARP1, PARP2 and PARP3 enzymes which are approved for the treatment of certain ovarian and breast cancers. The primary purpose of this study is to determine the maximum tolerated dose (MTD) of orally administered RBN-2397 in patients with advanced or metastatic solid tumors. This study will also evaluate the safety and tolerability of RBN-2397, examine the pharmacokinetics (PK) (measure how the body absorbs, breaks down and eliminates RBN-2397) and investigate whether it has antitumor activity in solid tumor cancers.

Detailed Description
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This is a first-in-human, Phase 1, multi-center, open-label, dose-escalation study to: Evaluate the safety profile and MTD of RBN-2397 administered orally and establish the RBN-2397 dose(s) and schedule(s) recommended for further investigation in Phase 2 Characterize the PK profile of RBN-2397 Identify preliminary antitumor activity. Biomarkers and their correlation with response to RBN-2397 and other outcomes will be examined. Cohorts will follow a traditional 3 + 3 design. After enrollment of the first participant within a cohort, there must be a wait period of at least 1 week before enrollment of additional participants in that cohort. This dose escalation phase of the study is complete. The study is currently in the Relative Bioavailability and Expansion Cohort(s) phase where approximately 20 participants each will be enrolled to further examine the safety, PK, pharmacodynamics, and antitumor activity of RBN-2397 at the recommended phase 2 dose. Relative Bioavailability Assessment: An evaluation of relative bioavailability of a micronized RBN-2397 tablet versus the standard RBN-2397 tablet (manufactured with unmicronized RBN-2397 and used in the dose escalation phase of the study) will be performed as part of the dose escalation phase. Micronized tablets will be used in the Dose Expansion Phase of the study after the relative bioavailability assessment has been completed. Dose Expansion Phase The recommended phase 2 dose will be investigated in the following cancer types: squamous cell carcinoma of the lung (SCCL), head and neck squamous cell carcinoma (HNSCC), hormone receptor positive (HR+) breast cancer, and PARP7 amplified cancer. Duration of treatment: It is anticipated that the minimum study involvement will be one cycle. Participants are eligible to have an indefinite number of additional cycles of treatment if their disease does not progress and they do not have unacceptable side effects.

Official Title
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A Phase 1, First-in-human Study of the Safety, Single- and Multiple-Dose Pharmacokinetics, and Preliminary Activity of Escalating Doses of RBN-2397, an Oral PARP7 Inhibitor, in Patients With Solid Tumors

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Drug: RBN-2397


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose Escalation Phase only: Metastatic or advanced-stage solid malignant tumor (which may include solid lymphoma [e.g., mantle cell]) for whom no therapy exists that would be curative or might provide clinical benefit. Dose Expansion Phase Only: Patients with locally advanced or metastatic solid tumors, with at least one measurable lesion as determined by RECIST version 1.1, who have received standard therapy or are intolerant of standard therapy, have progressed following their last prior therapy, and have one of the following tumor types: SCCL: Histologically confirmed NSCLC of predominantly squamous cell histology and must have received no more than 3 lines of prior systemic therapy including chemotherapy regimens and/or immune checkpoint inhibitor therapy (combination allowed). HNSCC: Histologically confirmed squamous cell carcinoma of the head and neck (either HPV-positive or -negative) and must have received no more than 3 lines of prior systemic immunotherapy and/or chemotherapeutic treatments in the metastatic setting. Includes primary tumor location of the oral cavity, oropharynx, hypopharynx, larynx, and paranasal sinuses (nasopharyngeal carcinoma, skin squamous cell carcinoma, and salivary gland carcinomas are not eligible). HR+ breast cancer: Histologically confirmed diagnosis of estrogen receptor (ER) and/or progesterone receptor (PR) positive, HER2-negative adenocarcinoma of breast (as per local laboratory testing) whose disease has failed standard systemic therapy for locally advanced or metastatic disease and must have received no more than 1 prior chemotherapeutic for advanced/metastatic disease. PARP7 amplified: Tumor with documented PARP7 (or TIPARP) gene copy amplification as determined by a CLIA certified laboratory test (e.g., FoundationOne CDx) that has failed standard systemic therapy for locally advanced or metastatic disease. Must agree to undergo tumor biopsy Normal organ and bone marrow function Patient and his/her partner agree to use adequate contraception during and for 3 months after the last study drug dose Exclusion Criteria: Unable to swallow oral medications Major surgery within 4 weeks of starting study Pregnant or breast-feeding. Receiving intravenous antibiotics for an active infection Known human immunodeficiency virus (HIV) or hepatitis B or C infection. History of a different malignancy unless disease-free for at least 5 years Some medications are not allowed while on study. Interested participants will need to inform study doctor of all the medications he/she is taking. Herbal medicines, and grapefruit, grapefruit juice, pomegranate juice, star fruit or orange marmalade (made with Seville oranges) are not allowed to be taken during study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Expansion
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RBN-2397<br>Dose Escalation: Multiple doses of RBN-2397 for oral administration Dose Expansion: Oral dose of RBN-2397 as determined during Dose Escalation | Drug: RBN-2397<br>* an oral PARP7 Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | Incidence of Dose limiting Toxicities (DLTs) | through first treatment cycle (an average of 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Grade and frequency of adverse events and serious adverse events | through study completion (an average of one year) | 
| Area under the plasma concentration for tablet manufactured with micronized RBN-2397 relative to unmicronized RBN-2397 (standard tablet) (Relative Bioavailability Cohorts only) | Area-under-the-curve (AUC inf) | Through Study Day 22 | 
| Peak plasma concentration for tablet manufactured with micronized RBN-2397 relative to unmicronized RBN-2397 (standard tablet) (Relative Bioavailability Cohorts only) | Cmax | Through Study Day 22 | 
| Antitumor activity that may be associated with RBN-2397 treatment assessed by CT/MRI Response Evaluation Criteria for Solid Tumors (RECIST) Criteria v1.1 | Objective response rate (ORR) | Every 6-8 weeks; through study completion (an average of one year) | 
| Antitumor activity that may be associated with RBN-2397 treatment | Disease control rate (DCR) | Every 6-8 weeks; through study completion (an average of one year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, PARP7 inhibition, First in Human, Solid Tumors, Interferon