Study of Glembatumumab Vedotin in gpNMB-Expressing, Advanced or Metastatic SCC of the Lung

Study Overview
=================
Brief Summary
-----------------
Patients with advanced or metastatic, gpNMB-expressing Squamous Cell Carcinoma (SCC) of the lung who have failed a prior platinum-based chemotherapy regimen will receive glembatumumab vedotin. Glembatumumab vedotin consists of an antibody (a type of human protein) attached to a drug called Monomethyl Auristatin E (MMAE) that can kill cancer cells. Glembatumumab vedotin is intended to work by specifically directing the drug to the cancer cell. It attaches to a molecule on the cancer cell called gpNMB, and then releases the MMAE inside the tumor cell, which in turn causes the cell to die. The purpose of this study is to see whether glembatumumab vedotin is effective in treating people who have advanced or metastatic squamous cell lung cancer that contains gpNMB, to examine how the body handles the drug and the side effects associated with glembatumumab vedotin.

Detailed Description
-----------------
Lung cancer is the most frequent cancer in the world, with annual cases worldwide currently estimated at one million and increasing to 10 million by the year 2025. In the United States, despite the declining incidence in white males in recent years, lung cancer is still the second most frequent cancer in both men (next to prostate) and women (next to breast cancer). This is an open-label, single arm study of glembatumumab vedotin, a fully-human IgG2 monoclonal antibody. The activity of glembatumumab vedotin may be greatest in patients who overexpress the target, gpNMB. This study will include a dose-escalation phase to determine the maximum safe and tolerated dose. This will be followed by a 2-stage Phase II expansion. During Phase II Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve a tumor response [Partial Response (PR) or Complete Response (CR)]; an additional 15 eligible, treated patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated patients. Glembatumumab vedotin will be administered once every 3 weeks, as a 90-minute intravenous (IV) infusion. Patients will continue treatment until disease progression or intolerance. Tumor assessments will be performed every six (±1) weeks for six months, and every nine (±2) weeks thereafter, until progression. A tumor tissue sample (i.e., obtained during a previous procedure or biopsy) will be sent to a central laboratory and tested for gpNMB. Research blood samples will also be required.

Official Title
-----------------
A Phase I/II Study of Glembatumumab Vedotin in Patients With gpNMB-Expressing, Advanced or Metastatic Squamous Cell Carcinoma of the Lung

Conditions
-----------------
Squamous Cell Carcinoma of the Lung

Intervention / Treatment
-----------------
* Drug: Phase I: Glembatumumab Vedotin
* Drug: Phase II: Glembatumumab Vedotin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures. Male or female patients with metastatic, histologically- or cytologically-confirmed unresectable Stage IIIB or IV non-small cell lung cancer (NSCLC) of squamous histology (Staging per American Joint Committee on Cancer [AJCC], Edition 7). Mixed histology adenosquamous NSCLC will also be permitted. Experienced progression/recurrence of disease during or subsequent to the most recent anti-cancer regimen. Any number of prior lines of systemic therapy may have been received for advanced (recurrent, locally advanced, or metastatic) SCC of the lung, but at least one must have been a platinum-based chemotherapy regimen. Platinum therapy may be given on-label or as part of a clinical trial. Lung cancer confirmed to express gpNMB, as assessed by immunohistochemistry at a central lab (using expression in ≥ 5% of tumor epithelial cells as a cut-off for positivity). This can be tested on archived tissue if available, although preferred tumor specimen is a biopsy after the most recent therapy. Age ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1. Measurable disease by RECIST 1.1 criteria. Target lesions selected for tumor measurements should be those where surgical resection or radiation are not indicated or anticipated. Resolution of all toxicities related to prior therapies to ≤ NCI-CTCAE Grade 1 severity, except for alopecia, vitiligo, or endocrinopathies on replacement therapy. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) ≥ 1500/mm3; hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3. Adequate renal function as assessed by serum creatinine ≤ 2.0 mg/dL; or calculated or 24-hour urine creatinine clearance >40 mL/min. Serum albumin ≥ 3 g/dL. Adequate liver function as assessed by total bilirubin ≤ 1.5x upper limit of normal (ULN), and alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5x ULN (≤ 5.0x ULN in the case of liver metastases). Patients with known Gilbert's syndrome may be enrolled with total bilirubin ≤ 3.0 mg/dL. Both male and female patients of childbearing potential enrolled in this trial must use adequate birth control measures during the course of the trial and for at least one month after discontinuing study drug. Willing to provide blood samples for research purposes. Exclusion Criteria: Received glembatumumab vedotin (CR011-vcMMAE; CDX-011) or other MMAE-containing agents previously. Chemotherapy within 21 days or at least 5 half-lives prior to the planned start of study treatment; radiation outside the thorax within 14 days prior to the planned start of study treatment or thoracic radiation; antibody based therapy or investigational therapy within 28 days prior to the planned start of study treatment. Neuropathy >NCI-CTCAE Grade 1. Subjects with a history of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin. Compounds of similar composition include Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and Symplostatin 1 as an anti-tumor agent. Known brain metastases, unless previously treated and patients are neurologically returned to baseline except for residual signs and symptoms related to Central Nervous System (CNS) treatment and CNS lesions are not progressive in size and number for 4 weeks. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, and congestive heart failure related to primary cardiac disease, a history of a serious uncontrollable arrhythmia despite treatment, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry. Active systemic infection requiring treatment. Infection controlled by oral therapy will not be exclusionary. Subjects on immunosuppressive medications such as azathioprine, mycophenolate mofetil, cyclosporine or require chronic corticosteroid use (defined as ≥ 3 months of prednisone dose equivalent of ≥ 10 mg). The MMAE component of glembatumumab vedotin is primarily metabolized by CYP3A. Patients taking strong CYP3A inhibitor and inducers are excluded in Phase I (the dose escalation portion), to minimize the effect of these modulators on exposure, tolerability and dose selection. History of other malignancy except for adequately treated basal or squamous cell skin cancer, curatively treated in situ disease, or any other cancer from which the patient has been disease-free for ≥ 2 years. Pregnant or breast-feeding women. Subjects must not be on home oxygen therapy (intermittent or continuous). Any underlying medical condition that, in the Investigator's opinion, will make the administration of study treatment hazardous to the patient, or would obscure the interpretation of adverse events.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Glembatumumab Vedotin<br>Glembatumumab vedotin once every three weeks (q3w) by 90-minute intravenous (IV) infusion, until disease progression or intolerance. The Dose-Limiting Toxicity (DLT) evaluation period for determination of the appropriateness of dose-escalation will be through the end of the second treatment cycle. | Drug: Phase I: Glembatumumab Vedotin<br>* Escalation Phase: Three to 6 patients will be enrolled in each dose cohort based on a standard Phase I dose escalation scheme. For the dose-escalation, the starting dose of glembatumumab vedotin will be 1.9 mg/kg q3w (Cohort 1). In the event of ≥ 2 DLTs, the dose will de-escalate to Cohort -1 (1.3 mg/kg). Dose escalation from Cohort 1 to Cohort 2 (2.2 mg/kg) may proceed if three patients in Cohort 1 complete the DLT observation period with 0 DLTs, or if six patients in Cohort 1 complete the DLT observation period with 0 or 1 DLTs.<br>* Other names: CDX-011; CR011-vcMMAE;|
| Experimental: Phase II: Glembatumumab Vedotin<br>Glembatumumab vedotin once every three weeks (q3w) by 90-minute intravenous (IV) infusion, until disease progression or intolerance. The Maximum Tolerated Dose (MTD) determined in Phase I will be used in Phase II. | Drug: Phase II: Glembatumumab Vedotin<br>* In Stage 1, approximately 20 eligible, treated patients will be enrolled. If ≥ 2 patients achieve a tumor response (Partial Response [PR] or Complete Response [CR]), an additional 15 eligible, treated patients will be enrolled in Stage 2, for a maximum total of 35 eligible, treated patients.<br>* Other names: CDX-011; CR011-vcMMAE;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Determine Maximum Tolerated Dose (MTD) | To determine the Maximum Tolerated Dose (MTD) by number of participants with DLTs. | 42 (±3) days | 
| Phase II: Objective Response Rate (ORR) | Determine the anti-tumor activity, as assessed by ORR in accordance with RECIST 1.1, of the MTD of glembatumumab vedotin in patients with advanced gpNMB-expressing SCC of the lung. | 40 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0. | To further characterize the safety of glembatumumab vedotin by the number of participants with abnormal laboratory values and/or adverse events related to treatment (including Serious Adverse Events and Other Adverse Events). | 23 months | 
| Duration of Objective Response (DOR) | DOR assessed in accordance with RECIST 1.1. | 23 months | 
| Progression-Free Survival (PFS) | PFS assessed in accordance with RECIST 1.1. | 23 months | 
| Overall Survival (OS) | OS assessed in accordance with RECIST 1.1. | 23 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
gpNMB-Expressing Squamous Cell Carcinoma of the Lung, Stage IIIb, Stage IV, Advanced Squamous Cell Cancer of the Lung, Metastatic Squamous Cell Cancer of the Lung, gpNMB-Expressing, Glembatumumab Vedotin