Safety and Efficacy Study of IMSA101 in Refractory Malignancies

Study Overview
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Brief Summary
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Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor (ICI) (Phase I and II)

Detailed Description
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This is an open-label, dose escalation (Phase I), and dose expansion (Phase IIA) study designed to evaluate safety and efficacy of IMSA101 alone or in combination with an ICI (Phase I and II). Therefore, the study will be conducted in 2 phases. The dose of IMSA101 in Phase IIA will be based on the monotherapy and combination Recommended Phase 2 Doses (RP2Ds) from Phase I. The following methodology applies to all patients (unless otherwise indicated): Pre-treatment screening radiographic tumor assessments will be collected within 30 days prior to initial dose for all patients. Photographic assessments for cutaneously-accessible lesions will be performed as detailed in a separate photography manual. Treatment cycles will be 28 days in duration with lesions injected weekly on Day 1 for the first three weeks of Cycle 1 and then every 2 weeks during cycles 2 and beyond. A single pre-defined lesion/lesion site (longest diameter ≥ 10 mm and ≤ 35 mm) shall be injected throughout study duration, if possible. Where the original injection site is considered by the investigator to become inaccessible, a second lesion/lesion site shall be selected as a replacement and this shall be used henceforth so long as it is considered accessible. Subsequent injection sites shall be replaced when they are considered inaccessible. Where no remaining accessible lesions are present and where benefit of IMSA101 therapy is, in the opinion of the investigator, being derived by the patient, continued injections of IMSA101 into the vicinity of an inaccessible lesion or, in the case that a lesion can no longer be radiographically visualized, into the last known location of the non-visible lesion shall be allowed. Patients will be admitted to the hospital for observation overnight following IT injection with IMSA101 on Day 1 of Cycle 1. Patients will be followed throughout the study for drug tolerability and safety by collection of clinical and laboratory data, including information on adverse events (AEs) using CTCAE v5.0 criteria, serious adverse events (SAEs), DLTs, concomitant medications, vital signs, and electrocardiograms (ECGs). Patients will be assessed for anti-tumor efficacy based on radiographic assessments and if applicable, photographic tumor assessments, and analysis of Objective Response Rate (ORR), Time to Progression (TTP), and Progression Free Survival (PFS) using RECIST criteria (Appendix 13.2) at screening and the end (≤ 7 days) of even numbered cycles (Cycle 2, Cycle 4, etc.) after the first dosing.

Official Title
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Phase I/IIA Safety and Efficacy Study of IMSA101 in Patients With Advanced Treatment-Refractory Malignancies

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Drug: IMSA101
* Drug: Immune checkpoint inhibitor (ICI)
* Drug: Immuno-oncology (IO) therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent and mental capability to understand the informed consent Male or female patients > 18 years of age Histologically or cytologically documented locally advanced or metastatic solid tumor malignancies refractory to or otherwise ineligible for treatment with standard-of-care agents/regimens, including but not limited to: Malignant melanoma Hormone receptor negative breast cancer Gastro-esophageal cancer Non-small cell lung cancer Head and neck cancer Hepatoma Renal cell carcinoma Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 Evaluable or measurable disease as follows: A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and biopsied; one non-injected that will be biopsied for abscopal effect; and one measurable lesion that will be followed for response only. Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous injection only, including those lesions that are visible, palpable, or detectable by standard radiographic or ultrasound methods. Neither surgical procedures nor endoscopically-guided injections including those to endobronchial, endoluminal, or endosinusial spaces shall be allowed. While no anatomic locations are required or disallowed, lesions selected for intratumoral injection must, in the opinion of the investigator: Not be immediately adjacent to blood vasculature or other physiologic landmarks in such a way that will accrue undue safety risk to the patient Have longest diameter ≥ 10 mm and ≤ 50 mm Be fully efficacy evaluable per RECIST v1.1 criteria Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA) ECG without evidence of clinically meaningful conduction abnormalities or active ischemia as determined by the investigator Acceptable organ and marrow function as defined below: Absolute neutrophil count > 1,500 cells/μL Platelets > 50,000 cells/μL Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If liver metastases are present, AST/ALT < 5 times ULN Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault formula Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN Women of child-bearing potential (defined as a female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months with an appropriate clinical profile at the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy test prior to first dose of study drug Male and female patients with reproductive potential must agree to use two forms of highly effective contraception throughout the study Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events considered by the investigator to be drug-related. Exclusion Criteria: Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug. Failure to recover to Grade 1 or less from clinically significant AEs due to prior anti-cancer therapy. Known untreated brain metastases or treated brain metastases that have not been stable (scan showing no worsening of central nervous system (CNS) lesion[s] and no requirement of corticosteroids) ≥ 4 weeks prior to study enrollment Baseline prolongation of QT/QTc interval (QTc interval > 470) Uncontrolled intercurrent illness (including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations) that in opinion of the investigator would limit compliance with study requirements Women who are pregnant or breastfeeding Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI therapy.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase I includes a monotherapy arm and an immune checkpoint inhibitor (ICI) combination therapy arm Phase II includes three arms, Arm A monotherapy, Arm B immuno-oncology (IO) combination therapy, Arm C IO combination therapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ph I Monotherapy<br>Dose escalation design in which administered dose levels of IMSA101 as monotherapy will be escalated stepwise in successive cohorts of 3 to 6 patients per dose group (using a standard 3+3 study design) of IMSA101 until the RP2D or maximum tolerated dose (MTD) level is identified. The first patient enrolled in each dose level must complete the first two weeks of Cycle 1 prior to enrolling the second and third patients. Dose levels to be evaluated include (although not necessarily limited to) 100 µg (representing 1/60th of the pre-clinical Highest Non-Severely Toxic Dose [HNSTD] dose), 200 µg, 400 µg, 800 µg, and 1,200 µg. | Drug: IMSA101<br>* IMSA101 administered by intra-tumoral (IT) injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 and on Day 1 of Weeks 1 and 3 for all subsequent cycles.<br>|
| Experimental: Ph I Combination Therapy<br>Ph I combination dosing of IMSA101 shall be evaluated upon satisfaction of the following criteria: A given dose level (combo dose level 1) has been confirmed as safe for monotherapy dosing (i.e. 2/6 patients experience Cycle 1 DLT). The next higher dose level (combo dose level 2) has been confirmed as safe for monotherapy dosing (i.e. 2/6 patients experience Cycle 1 DLT). The dose level (combo dose level 1) is found to demonstrate adequate IMSA101 pharmacodynamic (PD) activity based on exploratory endpoints. Eligible patients shall have demonstrated RECIST stable disease through ≥ 4 consecutive cycles of an approved PD-1/PD-L1-targeted ICI with no Grade ≥ 3 CTCAE events considered to be drug-related. Safety evaluations and dose escalation of IMSA101 administered in combination with current therapy shall proceed in a manner consistent with monotherapy escalation and shall proceed independently of monotherapy dose escalation. | Drug: IMSA101<br>* IMSA101 administered by intra-tumoral (IT) injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 and on Day 1 of Weeks 1 and 3 for all subsequent cycles.<br>Drug: Immune checkpoint inhibitor (ICI)<br>* Administered according to product label<br>|
| Experimental: Ph II Monotherapy (Arm A)<br>This dose-expansion arm of 20 patients is intended to confirm the tolerability of the RP2D and identify provocative signals of IMSA101 anti-tumor activity when administered as monotherapy Tumor type to be evaluated will be identified prior to Phase IIA commencement and will be documented in a protocol amendment. | Drug: IMSA101<br>* IMSA101 administered by intra-tumoral (IT) injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 and on Day 1 of Weeks 1 and 3 for all subsequent cycles.<br>|
| Experimental: Ph II Combination Therapy (Arm B)<br>This dose-expansion arm of 20 patients is intended to confirm the tolerability of the RP2D and identify provocative signals of IMSA101 anti-tumor activity when administered as combination therapy with PD-1/PD-L1 targeted immune checkpoint inhibitors. This arm shall include a safety run-in of 5-10 patients. Tumor type and corresponding treatment combination will be identified prior to Phase IIA commencement and documented in a protocol amendment. | Drug: IMSA101<br>* IMSA101 administered by intra-tumoral (IT) injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 and on Day 1 of Weeks 1 and 3 for all subsequent cycles.<br>Drug: Immune checkpoint inhibitor (ICI)<br>* Administered according to product label<br>|
| Experimental: Ph II Combination Therapy (Arm C)<br>This dose-expansion arm of 20 patients is intended to confirm the tolerability of the RP2D and identify provocative signals of IMSA101 anti-tumor activity when administered as combination therapy with non-PD-1/PD-L1-targeted immuno-oncology (IO) drugs approved by the FDA. This arm shall include a safety run-in of 5-10 patients. Tumor type and corresponding treatment combination will be identified prior to Phase IIA commencement and documented in a protocol amendment.. | Drug: IMSA101<br>* IMSA101 administered by intra-tumoral (IT) injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 and on Day 1 of Weeks 1 and 3 for all subsequent cycles.<br>Drug: Immuno-oncology (IO) therapy<br>* Administered according to product label<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | Number of adverse events and dose limiting toxicities per CTCAE v 5.0 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Sampling (Ph I) | Area under the curve minimum plasma concentration | 2 years | 
| Pharmacokinetic Sampling (Ph I) | Maximum plasma concentration | 2 years | 
| Pharmacokinetic Sampling (Ph I) | Elimination half life | 2 years | 
| Anti-tumor Effects | Tumor response, based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response. | 4 years | 
| Anti-tumor Effects | Duration of response (DOR), based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response. | 4 years | 
| Anti-tumor Effects | Time to tumor progression (TTP), based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response. | 4 years | 
| Anti-tumor Effects | Progression free survival (PFS), based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response. | 4 years |