NL-201 Monotherapy and in Combination With Pembrolizumab in Patients With Relapsed or Refractory Cancer

Study Overview
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Brief Summary
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Parts 1 and 2 The primary purpose of this study is to understand the safety of NL-201 when given intravenously as monotherapy in patients with advanced cancer to evaluate tolerability and to identify a recommended dose and schedule for further testing. In Part 1, there will be backfill cohorts at certain DMC-cleared dose levels and schedules to collect PK, PD and response data in certain tumor types or to explore additional pre-medication regimens. Parts 3 and 4 The primary purpose of this study is to understand the safety of NL-201 in combination with pembrolizumab when both drugs are given intravenously in patients with advanced cancer, to evaluate tolerability, and to identify a recommended dose and schedule for further testing.

Detailed Description
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Patients will have tests and exams to see if they are eligible for the clinical trial. Parts 1 and 2 If eligible, the patient will receive NL-201 treatment by vein. Tumor response to treatment will be assessed every 6 weeks for 12 weeks, and every 12 weeks thereafter until disease progression. Patients will be able to receive study treatment as long as it is tolerated and there is evidence of clinical benefit. Safety follow-up will occur within 7 days after the last dose of NL-201. Patients will then enter long-term follow-up until starting a subsequent therapy. In Part 1, there will be backfill cohorts at certain DMC-cleared dose levels and schedules to collect PK, PD and response data in certain tumor types or to explore additional pre-medication regimens. Parts 3 and 4 If eligible, the patient will receive NL-201 and pembrolizumab treatment by vein. Tumor response to treatment will be assessed every 6 weeks for 12 weeks, and every 12 weeks thereafter until disease progression. Patients will be able to receive study treatments as long as they are tolerated and there is evidence of clinical benefit. Safety follow-up will occur within 7 days after the last dose of investigational product. Patients will then enter long-term follow-up until starting a subsequent therapy.

Official Title
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A First-in-Human Phase 1 Study of NL-201 Monotherapy and in Combination With Pembrolizumab in Patients With Relapsed or Refractory Cancer

Conditions
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Solid Tumor, Advanced Solid Tumor

Intervention / Treatment
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* Drug: NL-201
* Drug: Pembrolizumab Injection [Keytruda]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with measurable disease Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 At least 6 weeks from any prior nitrosurea or mitomycin C therapy; at least 4 weeks from any other prior chemotherapy or checkpoint inhibitor; at least 2 weeks from any kinase inhibitor Part 1 Only: Patients with relapsed or refractory advanced solid tumor, other than prostate cancer, who have progressed, not tolerated or are ineligible for all approved lines of therapy Part 2 Only: Patients with kidney and skin cancer who have failed at least 1 line of systemic therapy Part 3 Only: Patients with solid tumors who have received ≥ 1 prior line of therapy for advanced or metastatic disease Part 4 Only: Patients with diagnosed target disease OR previously received pembrolizumab Exclusion Criteria: Prostate Cancer Any serious medical condition or laboratory abnormality or psychiatric condition or any other significant or unstable concurrent medical illness (in the opinion of the Investigator) would preclude protocol adherence or would make the safety of the study drug difficult to assess Known or suspected SARS-CoV-2 infection, unless patient tests negative for SARS-CoV-2 within the Screening period History of solid organ transplant or bone marrow transplant Prior CAR-T or allogeneic cellular therapy Prior IL-2-based cancer therapy Ongoing systemic immunosuppressive therapy Concurrent therapy with any other investigational agent, vaccine, or device. Part 3 and 4 Only: History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Part 3 and 4 Only: Known additional cancer that is progressing or has required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone curative resection are eligible.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: NL-201 Monotherapy Dose Escalation<br>NL-201 given as monotherapy by intravenous administration testing ascending doses and two different schedules. | Drug: NL-201<br>* NL-201 is a de novo protein therapeutic.<br>|
| Experimental: Part 2: NL201 Monotherapy Expansion Cohorts<br>NL-201 given as monotherapy by intravenous administration in indication specific cohorts at a dose and schedule determined in Part 1. | Drug: NL-201<br>* NL-201 is a de novo protein therapeutic.<br>|
| Experimental: Part 3: NL-201 in Combination with Pembrolizumab Dose Escalation<br>NL-201, in combination with a set Pembrolizumab dose, testing ascending doses and two different schedules | Drug: NL-201<br>* NL-201 is a de novo protein therapeutic.<br>Drug: Pembrolizumab Injection [Keytruda]<br>* A programmed death receptor-1 (PD-1)-blocking antibody<br>* Other names: MK-3475, Pembrolizumab, Keytruda;|
| Experimental: Part 4: NL-201 in Combination with Pembrolizumab Expansion Cohorts<br>NL-201 in combination with Pembrolizumab in indication specific cohorts at a dose and schedule determined in Part 3 | Drug: NL-201<br>* NL-201 is a de novo protein therapeutic.<br>Drug: Pembrolizumab Injection [Keytruda]<br>* A programmed death receptor-1 (PD-1)-blocking antibody<br>* Other names: MK-3475, Pembrolizumab, Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase 2 dose (RP2D) for NL-201 (Parts 1 and 2) | Evaluation of tolerability of NL-201 as measured by number of subjects with dose limiting toxicities (DLTs) | Up to Day 33 | 
| Recommended dose schedule for NL-201 (Parts 1 and 2) | Evaluation of tolerability of NL-201 as measured by number of subjects with dose limiting toxicities (DLTs) | Up to Day 33 | 
| Recommended phase 2 dose (RP2D) for NL-201 in combination with Pembrolizumab (Parts 3 and 4) | Evaluation of tolerability of NL-201 in combination with Pembrolizumab as measured by number of subjects with dose limiting toxicities (DLTs) | Up to Day 33 | 
| Recommended dose schedule for NL-201 in combination with Pembrolizumab (Parts 3 and 4) | Evaluation of tolerability of NL-201 in combination with Pembrolizumab as measured by number of subjects with dose limiting toxicities (DLTs) | Up to Day 33 | 
| Incidence of treatment-emergent adverse events | Rate of adverse events in patients with advanced solid tumors | Up to Day 33 | 
| Severity of treatment-emergent adverse events | Rate of adverse event grades in patients with advanced solid tumors | Up to Day 33 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Objective Response according to RECIST version 1.1 | Based on Investigator assessment of radiographic imaging | Up to 36 months | 
| Objective Response Rate (ORR) according to RECIST version 1.1 | Based on Investigator assessment of radiographic imaging | Up to 36 months | 
| Progression-Free Survival (PFS) according to RECIST version 1.1 | Based on Investigator assessment of radiographic imaging | Up to 36 months | 
| Duration of Response (DOR) according to RECIST version 1.1 | Based on Investigator assessment of radiographic imaging | Upto 36 months | 
| Pharmacokinetic (PK) profile of NL-201 by half-life (t1/2) | Prespecified timepoints in serum before and after dosing with NL-201. | Up to 24 Months | 
| Pharmacokinetic (PK) profile of NL-201 by area under the plasma concentration time curve (AUC) | Prespecified timepoints in serum before and after dosing with NL-201. | Up to 24 months | 
| Pharmacokinetic (PK) profile of NL-201 by maximum observed plasma concentration (Cmax) | Prespecified timepoints in serum before and after dosing with NL-201. | Up to 24 months | 
| Pharmacokinetic (PK) profile of NL-201 by volume of distribution (Vd) | Prespecified timepoints in serum before and after dosing with NL-201. | Up to 24 Months | 
| Terminal-Phase Elimination Rate Constant (β) of NL-201 | Prespecified timepoints in serum before and after dosing with NL-201. | Up to 24 months | 
| Immunogenicity of NL-201 | Anti-drug antibodies in serum during and after treatment with NL-201 | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, NL-201, NL201-101, Phase 1, Immunotherapy, Cytokine, Pembrolizumab, Keytruda, IL-2, IL-15, MK-3475