Study to Evaluate the Safety and Efficacy of Oral NRC-2694-A in Combination With Paclitaxel in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma, Who Progressed on or After Immune Checkpoint Inhibitor Therapy

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multicenter, single-arm study of NRC-2694-A in combination with paclitaxel in patients with R/M HNSCC with progression on or after ICI therapy. A total of approximately 46 male and female patients will be enrolled. This sample size is based on Simon's 2-stage design with historical control ORR of 30% and a target ORR of 50%.

Detailed Description
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Patients with recurrent and/or metastatic unresectable Head and Neck Cancer have a poor prognosis and limited treatment options. Pembrolizumab and Nivolumab, both ICIs (Immune Checkpoint Inhibitors), are approved therapies for this condition. However, no approved treatment options exist for patients who progress on ICI therapies. Hence, there is an unmet medical need post-failure of ICI therapy. NRC-2694-A is an orally administered small-molecule tyrosine kinase inhibitor. It was discovered and developed by NATCO Pharma Ltd. NRC-2694-A demonstrated response in HNSCC patients in a Phase-I study as a monotherapy. This was further substantiated in a Phase-II study in combination with cisplatin/carboplatin and paclitaxel.

Official Title
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A Phase 2 Multicenter, Open-Label, Single-Arm Study to Evaluate the Safety and Efficacy of Oral NRC-2694-A in Combination With Paclitaxel in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma, Who Progressed on or After Immune Checkpoint Inhibitor Therapy

Conditions
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Carcinoma, Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: NRC-2694-A
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is willing and capable of understanding the written informed consent, provides signed and witnessed written informed consent, and agrees to comply with protocol requirements. Is male or female aged 18 years or older at the time of consent. Has histologically confirmed unresectable R/M HNSCC (oral cavity, oropharynx, hypopharynx, and larynx). Has documented radiographical progressive disease assessed by the principal investigator per RECIST v1.1. Has a measurable lesion per RECIST v1.1. Has ECOG performance status score of ≤2. Must have progressed during or after receiving ICI therapy, such as pembrolizumab or nivolumab. Patients with prior immune-mediated reactions due to ICI therapies (eg, pembrolizumab or nivolumab) and who had recovered prior to study entry will also be eligible. Female patients of childbearing potential should have a negative urine test before enrollment. If the urine pregnancy test is positive or gives equivocal results, a serum pregnancy will be required for confirmation. Patients of reproductive age must use acceptable methods of contraception throughout the study period and for 30 days following the last dose of investigational product (see protocol for further guidance). During screening and at subsequent visits, the investigator should ensure adequate bone marrow reserve (neutrophil count ≥1500/mm3, platelet count ≥100,000/mm3, and hemoglobin level 8.0 g/dL), renal function (creatinine clearance ≥50 mL/min calculated by Cockcroft-Gault formula), liver function (total bilirubin level ≤1.5 × ULN [except patients with documented Gilbert's syndrome] and serum transaminase levels ≤2.5 × ULN or ≤5 × ULN for liver metastasis and/or obstructive jaundice). Must have completed a duration of at least 4 weeks after stopping ICI therapy and must have recovered to grade ≤1 from all toxicities due to this therapy. Exclusion Criteria: Has cardiac, hepatic, endocrine, pulmonary, or autoimmune disease, interstitial lung disease, renal or psychiatric disorders, not controlled with therapy corresponding to the illness or a condition that contraindicates the use of a taxane or an EGFR inhibitor. Has uncontrolled brain metastases. Patients are allowed if brain metastasis has been previously treated with surgery, whole brain irradiation, and/or stereotactic radiosurgery and are considered controlled (controlled by the dose ≤10 mg/day of prednisone or equivalent) at the time of the first dose of investigational product. Radiological evaluation of brain metastasis will be performed only if the patient has symptoms. For asymptomatic patients, brain imaging during screening is not required. Has baseline prolongation of QT/QTc interval (eg, repeated demonstration of a QTc interval >480 milliseconds [CTCAE Grade 1] using Fredericia's QT correction formula). Has a history of additional risk factors for Torsade de pointes (eg, heart failure, hypokalemia, family history of long QT syndrome). Has had prior cetuximab therapy for recurrent or metastatic disease. Note that cetuximab used concomitantly with radiotherapy or as an induction therapy is acceptable Has received any other EGFR-targeted therapies for recurrent or metastatic disease. Currently participating in any clinical trial or receiving investigational therapy on expanded access or compassionate basis. Has nasopharyngeal carcinomas or salivary gland cancers. Has received investigational products or any other salvage therapy after failure of pembrolizumab/nivolumab therapy. Female patient who tested positive for pregnancy. Female patient who is breastfeeding or planning to become pregnant, or male patient planning to father a child within the duration of the study. Has tested positive for HIV, HBsAg, HCV antibody, or HCV RNA at screening. However, patients who test positive for HCV antibody, but negative for HCV RNA, will be allowed. In addition, patients with controlled HIV, chronic HBV on suppressive antiviral therapy, or a history of HCV infection status post-curative antiviral treatment with an HCV viral load below limit of quantification are permitted to participate (DHHS 2020). Has active infection requiring intravenous anti-infective therapy within 7 days prior to Day 1 Cycle 1 or is febrile due to infection. Has had major surgery within 4 weeks prior to screening. Administered a live attenuated vaccine within 4 weeks prior to Day 1 Cycle 1 or anticipation that such a live attenuated vaccine will be required during the study. Has known or suspected hypersensitivity to any components of the formulation used for this investigational product. Has concurrent disease or any clinically significant abnormality following the investigator's review of the screening physical examination findings, 12-lead ECG results, and clinical laboratory tests, which in the judgment of the investigator would interfere with the patient's participation in this study or evaluation of study results. Unable to come for study visits per schedule. Has current drug or alcohol abuse. Has received prior treatment with paclitaxel or docetaxel for metastatic or recurrent HNSCC. However, prior paclitaxel or docetaxel as a component of a curatively-intended multimodality treatment for locally advanced HNSCC is permitted.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NRC-2694-A In Combination with paclitaxel<br>Patients will receive NRC-2694-A 300 mg orally once daily and paclitaxel 175 mg/m² IV infusion over approximately 3 hours once in 21 days for 6 cycles or more. | Drug: NRC-2694-A<br>* 300 mg orally once daily<br>Drug: Paclitaxel<br>* 175 mg/m² IV infusion over approximately 3 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine if NRC-2694-A administered orally in combination with paclitaxel demonstrates objective response in patients with R/M HNSCC, who have had radiological progression on or after treatment with ICI therapies like pembrolizumab or nivolumab | Objective response in terms of CR/PR per RECIST v1.1 | Baseline through approximately up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | defined as the interval of time between the date of enrollment to the earliest date of disease progression, as determined by local radiologic assessment per RECIST v1.1, or death due to any cause, whichever occurs first | Baseline through approximately up to 24 weeks | 
| Overall survival | defined as the time from the date of enrollment to the date of death due to any cause | Baseline through approximately up to 24 weeks | 
| Duration of response | defined as the time from first confirmed objective response to disease progression | Baseline through approximately up to 24 weeks | 
| Clinical benefit response | defined as CR + PR + SD for ≥ 6 months | Baseline through approximately up to 26 weeks | 
| Number of adverse events |  | Baseline through approximately up to 24 weeks | 
| Number of participants with abnormal physical examination findings | Symptom-directed physical examination will be conducted to evaluate skin rash, diarrhea, paresthesia, and dyspnea graded according to NCI CTCAE version 5.0. | Baseline through approximately up to 24 weeks | 
| Number of participants with abnormal vital signs | Clinically significant abnormal blood pressure, heart rate, respiratory rate, and oral body temperature graded according to NCI CTCAE version 5.0. | Baseline through approximately up to 24 weeks | 
| Assessing safety through ECOG (Eastern Cooperative Oncology Group) | The severity of the AE will be graded according to the NCI CTCAE version 5.0 (NCI Common Terminology Criteria for Adverse Events. The CTCAE displays Grades 1 through Grade 5 with the higher score as worse outcome) | Baseline through approximately up to 24 weeks | 
| Number of participants with abnormal clinical laboratory tests results | Clinically significant abnormal hematology, biochemistry, coagulation and urinalysis test results graded according to NCI CTCAE version 5.0. | Baseline through approximately up to 24 weeks | 
| Number of participants with abnormal ECGs (Electrocardiograms) | Clinically significant abnormal ECG findings will be graded per NCI CTCAE version 5.0. | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via Cmax (Maximum plasma concentration) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via Tmax (time to reach the maximum plasma concentration) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via Ctrough (observed trough plasma concentration at the dosing interval tau) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via AUC0-t (area under the concentration-time curve from time zero to the time of last measurable concentration) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via AUC0-τ (area under the concentration-time curve from time zero to the dosing interval tau) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via CL/F (apparent clearance) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via Vz/F (apparent volume of distribution) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via Rac Cmax (accumulation ratio based on maximum plasma concentration) |  | Baseline through approximately up to 24 weeks | 
| Plasma PK parameters of NRC-2694-A measured via Rac AUC (accumulation ratio based on area under the concentration-time curve) |  | Baseline through approximately up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Carcinoma, Recurrent and/or Metastatic Cancer