Study of DF9001 in Patients With Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
DF9001-001 is a study of a new molecule that targets natural killer (NK) cells and T-cell activation signals to specific receptors on cancer cells. The study will occur in two phases. The first phase will be a dose escalation phase, enrolling patients with various types of solid tumors that express epidermal growth factor receptor (EGFR). A combination therapy cohort will be opened for enrollment, DF9001 + nivolumab. The second phase will include a dose expansion using the best dose selected from the first phase of the study. Multiple cohorts will be opened with eligible patients having selected solid tumors.

Official Title
-----------------
A Phase 1/2, Open-Label Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of DF9001 as a Monotherapy and in Combination With Nivolumab in Patients With Advanced Solid Tumors, and Expansion in Selected Indications

Conditions
-----------------
Solid Tumor, Adult

Intervention / Treatment
-----------------
* Drug: DF9001
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: General (applies to all cohorts) Signed written informed consent. Male or female patients aged ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry and an estimated life expectancy of at least 3 months. Adequate hematological function. Adequate hepatic function. Adequate renal function. Effective contraception for women of child bearing potential (WOCBP) patients as defined by World Health Organization (WHO) guidelines for 1 highly effective method or 2 effective methods. Inclusion Criteria: Dose Escalation (Monotherapy and Combination) Histologically or cytologically proven locally advanced or metastatic solid tumors of epithelial origin with documented EGFR expression on tumor tissue by IHC and must have progressed on standard of care therapy. Evidence of objective disease, but participation does not require a measurable lesion. Inclusion Criteria: Safety PK/PD Expansion Cohorts Histologically or cytologically proven locally advanced or metastatic solid tumor from the following list, where standard therapy has failed, that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. i. NSCLC ii. HNSCC iii. CRC iv. Esophageal adenocarcinoma v. Gastric cancer vi. Renal cell carcinoma vii. Pancreatic cancer Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. Able and willing to have a fresh tumor biopsy obtained during the screening window and an on-treatment biopsy for pharmacodynamic analysis. Inclusion Criteria: Head and Neck Squamous Cell Carcinoma (HNSCC) Expansion Cohorts Histologically or cytologically documented relapsed or metastatic HNSCC that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. Primary tumor locations include oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology). Participants must have radiographic disease progression while on or after having received both platinum-based chemotherapy and an anti-PD-(L)1 antibody, administered either concurrent or sequentially. Documented EGFR expression by IHC. Able and willing to have a fresh tumor biopsy obtained during the screening window and an on-treatment biopsy for pharmacodynamic analysis. Inclusion Criteria: Colorectal Cancer (CRC) Expansion Cohorts Histologically or cytologically documented relapsed or metastatic colorectal cancer that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. Must have received 1 line of either FOLFOX, CAPOX, FOLFIRI, or FOLFOXIRI with or without a biological agent. Prior treatment with an anti-EGFR antibody is required for RAS wild-type participants. Participants cannot be known mismatch repair (MMR)/MSI high. Participants must not have received an anti-PD-(L)1. Participants must have radiographic disease progression while or after receiving treatment for their advanced (recurrent/unresectable/metastatic) disease. Presence of at least 1 tumor lesion accessible for biopsy. A fresh tumor biopsy must be obtained and shipped for analysis at the Sponsor-designated laboratory during the screening window and while on study treatment in accordance with the study Laboratory Manual. Inclusion Criteria: Non-Small Cell Lung Cancer (NSCLC) Expansion Cohorts Histologically confirmed NSCLC meeting stage criteria for stage IIIB, stage IV (per the 7th IASCLC classification of NSCLC), or recurrent disease that has been confirmed to have EGFR expression via archival or fresh biopsy tissue prior to study enrollment. Patients must have recurrent or progressive disease during or after first line combination therapy with checkpoint inhibitors and platinum-based chemotherapy. They must not have received any subsequent lines of therapy. Patients with Stage IIIB must be ineligible for local therapies with curative intent (eg, radiotherapy or surgery). Patients must have received and progressed on or after anti-PD-(L)1 therapy including those with actionable genomic alterations. Status for actionable mutations (EGFR, ALK, ROS1, RET, etc.) must be known (when testing is available as per country/region standard of care practices); patients with actionable mutations must have received and progressed on, have been intolerant to, or not be a candidate for standard TKIs (as available per country/region standard of care practices). Presence of at least 1 tumor lesion accessible for biopsy. A fresh tumor biopsy must be obtained and shipped for analysis at the Sponsor-designated laboratory during the screening window and while on study treatment in accordance with the study Laboratory Manual. Exclusion Criteria: Participants must not have had chemotherapy, radiotherapy (other than palliative bone-directed radiotherapy), or major surgery, or received another investigational agent within 28 days or 5-half-lives of the drug (if known), whichever is shorter, before the start of study treatment. Concurrent anticancer treatment (eg, cytoreductive therapy, radiotherapy [except for palliative bone-directed radiotherapy], immune therapy, or cytokine therapy [except for erythropoietin]), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days or 5-half-lives of the drug (if known), whichever is shorter, before the start of study treatment. Short-term administration of systemic steroids (eg, for allergic reactions or the management of irAEs) is allowed. Note: Participants receiving bisphosphonate or denosumab are eligible, provided treatment was initiated at least 14 days before the first dose of DF9001. Previous malignant disease other than the target malignancy to be investigated in this study within the last 3 years, with the exception of basal or squamous cell carcinoma of the skin, low-grade prostate cancer (Gleason score of ≤6), or cervical carcinoma in situ. Life expectancy of less than 3 months. Participants with brain metastases are excluded, unless all of the following criteria are met: Central nervous system (CNS) lesions are asymptomatic, previously treated and no active therapy is required (i.e., no steroids for edema). Imaging demonstrates stability of disease 28 days from last treatment for CNS metastases. Receipt of any organ transplantation, including autologous or allogeneic stem-cell transplantation. Significant acute or chronic infections (including historic positive test for human immunodeficiency virus [HIV], or active or latent hepatitis B or active hepatitis C tested during the screening window). If HBsAg is negative and the anti-hepatitis B core antibody is positive, then hepatitis B viral DNA load must be undetectable. Preexisting autoimmune disease (except for participants with vitiligo) needing treatment with systemic immunosuppressive agents for more than 28 days within the last 3 years, or clinically relevant immunodeficiencies (eg, dysgammaglobulinemia or congenital immunodeficiencies). Participants with a history of immune related endocrinopathies (e.g. hypothyroidism, type 1 diabetes mellitus [TIDM] and adrenal insufficiency) that are stable on hormone replacement therapy may be eligible for this study. Participants with a known medical history that may place them at risk of known toxicities of EGFR-blockage. History of or ongoing keratitis, ulcerative keratitis, or corneal perforation, History of cardiopulmonary arrest unless this was caused by an acute, reversible etiology that is no longer present. History of or ongoing pulmonary fibrosis or interstitial lung disease. Known severe hypersensitivity reactions to monoclonal antibodies (≥Grade 3 of the NCI-CTCAE v5.0), any history of anaphylaxis, or uncontrolled asthma (ie, 3 or more features of partly controlled asthma). Persisting toxicity related to prior therapy >Grade 1 NCI-CTCAE v5.0; however, alopecia ≤Grade 2, endocrinopathies ≤Grade 2, and sensory neuropathy ≤Grade 2 is acceptable. Participants who have received an anti-PD-(L)1 as a previous line of therapy are eligible for the study, unless they have experienced either: a Grade 3 or 4 drug-related toxicity during and attributed to treatment with the anti-PD-(L)1. a Grade 2 drug-related toxicity that impacted either the lungs or the nervous system, caused by the administration of the anti-PD-(L)1. Pregnancy or lactation in females during the study. Known alcohol or drug abuse. Serious cardiac illness or medical conditions, including but not limited to: History of New York Heart Association class III or IV heart failure or systolic dysfunction (left ventricular ejection fraction [LVEF] <55%). High-risk uncontrolled arrhythmias (eg, tachycardia with a heart rate >100/min at rest). Significant ventricular arrhythmia (ventricular tachycardia) or higher-grade atrioventricular (AV) block (eg, AV-block, second degree AV block Type 2 [Mobitz 2], or third-degree AV-block). Angina pectoris requiring anti-anginal medication. Clinically significant valvular heart disease. Evidence of transmural infarction on ECGs. Poorly controlled hypertension (defined as systolic >160 mm Hg or diastolic >100 mm Hg). Clinically relevant uncontrolled cardiac risk factors, clinically relevant pulmonary disease, or any clinically relevant medical condition in the opinion of the Investigator that may limit participation in this study. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. All other significant diseases (eg, inflammatory bowel disease), which, in the opinion of the Investigator, might impair the participant's ability to participate. Any psychiatric condition that would prohibit the understanding or rendering of informed consent. Legal incapacity or limited legal capacity. Incapable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Monotherapy DF9001 Dose Escalation<br>Dose escalation cohorts of DF1001 in sequential ascending order. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>|
| Experimental: Monotherapy DF9001 PK/PD Expansion<br>Expansion cohorts of monotherapy DF9001 in multiple dose levels after evaluation for safety in Monotherapy Dose Escalation arm. Additional pharmacokinetic (PK) and pharmacodynamic (PD) samples included in this arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>|
| Experimental: Monotherapy DF9001 Expansion in Head and Neck Squamous Cell Carcinoma<br>Monotherapy expansion cohort enrolling up to 40 patients with head and neck squamous cell carcinoma (HNSCC) using the recommended phase 2 dose (RP2D) identified in the Monotherapy Dose Escalation arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>|
| Experimental: Monotherapy DF9001 Expansion in Colorectal Cancer<br>Monotherapy expansion cohort enrolling up to 40 patients with colorectal cancer (CRC) using the recommended phase 2 dose (RP2D) identified in the Monotherapy Dose Escalation arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>|
| Experimental: Monotherapy DF9001 Expansion in Non-small Cell Lung Cancer<br>Monotherapy expansion cohort enrolling up to 40 patients with Non-small cell lung cancer (NSCLC) using the recommended phase 2 dose (RP2D) identified in the Monotherapy Dose Escalation arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>|
| Experimental: Combination Escalation with DF9001 and nivolumab<br>Combination dose escalation of DF9001 in combination with a PD-1 checkpoint inhibitor in patients with select solid tumors. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>Drug: Nivolumab<br>* Anti-PD-1 immunotherapy agent<br>|
| Experimental: Combination PK/PD Expansion with DF9001 and nivolumab<br>Expansion cohorts of DF9001 in combination with a PD-1 checkpoint inhibitor in multiple dose levels after evaluation for safety in Monotherapy Dose Escalation arm. Additional pharmacokinetic (PK) and pharmacodynamic (PD) samples included in this arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>Drug: Nivolumab<br>* Anti-PD-1 immunotherapy agent<br>|
| Experimental: Combination Expansion of DF9001 and nivolumab in Head and Neck Squamous Cell Carcinoma<br>Combination expansion cohort using DF9001 and a PD-1 checkpoint inhibitor enrolling up to 40 patients with head and neck squamous cell carcinoma (HNSCC) using the recommended phase 2 dose (RP2D) identified in the Monotherapy Dose Escalation arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>Drug: Nivolumab<br>* Anti-PD-1 immunotherapy agent<br>|
| Experimental: Combination Expansion of DF9001 and nivolumab in Colorectal Cancer<br>Combination expansion cohort using DF9001 and a PD-1 checkpoint inhibitor enrolling up to 40 patients with colorectal cancer (CRC) using the recommended phase 2 dose (RP2D) identified in the Monotherapy Dose Escalation arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>Drug: Nivolumab<br>* Anti-PD-1 immunotherapy agent<br>|
| Experimental: Combination Expansion of DF9001 and nivolumab in Non-Small Cell Lung Cancer<br>Combination expansion cohort using DF9001 and a PD-1 checkpoint inhibitor enrolling up to 40 patients with non-small cell lung cancer (NSCLC) using the recommended phase 2 dose (RP2D) identified in the Monotherapy Dose Escalation arm. | Drug: DF9001<br>* Immunotherapy agent targeting NK cells.<br>Drug: Nivolumab<br>* Anti-PD-1 immunotherapy agent<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of number of dose limiting toxicities experienced on study as defined per criteria in the study protocol | To assess the number of adverse events experienced during the study that meet dose limiting toxicity criteria per the study protocol. | First 4 weeks of treatment for each subject. | 
| Assess Overall Response Rate | To assess the Overall Response Rate (ORR) per RECIST 1.1 criteria. | Through 90 days after completion of the study, an average of 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number, severity, and duration of treatment-related adverse events (TRAEs) according to NCI-CTCAE v5.0. | To assess the safety of DF9001 by measuring Number of subjects with Treatment-Related Adverse Events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Screening visit up to 28 days after last treatment on the study. | 
| Assess the safety and tolerability of DF9001 in combination with nivolumab. | To assess the safety of DF9001 in Combination therapy with nivolumab by measuring Number of subjects with Treatment-Emergent Adverse Events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 | Screening visit up to 28 days after last treatment on the study. | 
| Serum concentrations of DF9001 will be determined at various time points. | Concentration vs time of DF9001 will be measured using blood samples taken at various time points on study. | From start of treatment up through 7 days after the decision to stop study treatment. | 
| Characterize the pharmacodynamic profile of DF9001 as a monotherapy. | Changes to immune cell activation will be measured by flow cytometry performed on peripheral blood collected on study at sequential timepoints. | Prior to study treatment and 6 weeks after start of study treatment. | 
| Characterize the gene expression profile of DF9001 as a monotherapy. | Changes to the body's genetic profile related to immune responses will be measured by Nanostring RNA sequencing in tumor tissue collected before and during treatment. | Prior to study treatment and 6 weeks after start of study treatment. | 
| Characterize the pharmacodynamic profile of DF9001 in combination with nivolumab. | Changes to immune cell activation will be measured by flow cytometry performed on peripheral blood collected on study at sequential timepoints. | Prior to study treatment and 6 weeks after start of study treatment. | 
| Characterize the gene expression profile of DF9001 in combination with nivolumab. | Changes to the body's genetic profile related to immune responses will be measured by Nanostring RNA sequencing in tumor tissue collected before and during treatment. | Prior to study treatment and 6 weeks after start of study treatment. | 
| Evaluate the immunogenicity of DF9001. | Evaluate the immunogenicity of DF9001 by measuring the number of patients developing anti-DF9001 antibodies | Every 4 weeks up to 28 days after last treatment. | 
| Assess the best overall response (BOR) by IERC. | To assess Best Overall Response (BOR) | Through 90 days after completion of the study, an average of 1 year. | 
| Assess the duration of response (DOR) by IERC. | To assess Duration of Response (DOR) of DF9001 | From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months. | 
| Assess progression-free survival (PFS) for DF9001 per an IERC. | To assess Progression Free Survival (PFS) for DF9001 | From time of initiation of therapy until the date of first documented tumor progression, assessed up to 24 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EGFR, NK Cell, Immunotherapy, Non-Small Cell Lung Cancer, Colorectal Cancer, Head and Neck Squamous Cell Carcinoma