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VX15/2503 in Combination With Avelumab in Advanced Non-small Cell Lung Cancer (CLASSICAL-Lung)

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ClinicalTrials.gov Identifier: NCT03268057
Recruitment Status : Recruiting
First Posted : August 31, 2017
Last Update Posted : March 8, 2018
Sponsor:
Collaborator:
Merck KGaA/EMD Serono
Information provided by (Responsible Party):
Vaccinex Inc.

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of IV administration of VX15/2503 in combination with a fixed dose of avelumab in patients with advanced non-small cell lung cancer. The dose escalation portion of the study will determine the maximum tolerated dose (MTD) of VX15/2503 administered in combination with avelumab.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: VX15/2503 + avelumab Phase 1 Phase 2

Detailed Description:

This is a phase 1b/2 study, designed to evaluate the safety, tolerability, and efficacy of VX15/2503 in combination with avelumab in immunotherapy-naïve subjects diagnosed with advanced (stage IIIB/IV) NSCLC who have either progressed on cytotoxic chemotherapy or declined first-line treatment with cytotoxic chemotherapy. The primary objective (Dose Escalation Phase) is to evaluate the safety and tolerability of ascending doses of VX15/2503 Q2W in combination with avelumab 10mg/kg Q2W. The second primary objective (Dose Expansion Phase) is to evaluate safety and tolerability of teh recommended phase 2 dose of VX15/2503 administered in combination with 10 mg/kg avelumab Q2W. The secondary objectives include (Dose Expansion Phase), a preliminary estimate of efficacy using the following in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Objective Response (OR), Duration of Response (DoR) and Progression-Free Survival (PFS), as well as making a preliminary estimate of efficacy using the following in accordance with iRECIST, OR, DoR and PFS. Additional secondary objectives are to characterize the pharmacokinetics profile of VX15/2503 and avelumab administered Q2W in combination, evaluate the immunogenicity of VX15/2503 and avelumab administered Q2W and evaluate VX15/2503 and avelumab pharmacodynamics markers including but not limited to receptor occupancy. Exploratory objectives include identification of candidate biomarkers of activity and biomarkers that may predict response to treatment with combination therapy of VX15/2503 and avelumab.

Enrollment will involve approximately 40 individuals who are 18 years of age or older with advanced non-small cell lung cancer. The study will be divided into two phases, dose escalation with up to 18 patients and dose expansion with up to 28 subjects. Subjects that are enrolled in the dose escalation phase may continue into the dose expansion phase, as long as there is no evidence of disease progression. The subjects entering the dose expansion phase from dose escalation, may have their dose increased to the recommend phase 2 dose, once it is determined. Any subjects that have evidence of disease progression will be taken off of treatment and will have a post treatment safety follow-up visit 10 weeks after last treatment. Subjects that have discontinued study drug will also continue to be followed every 3 months for survival, or lost to follow-up. It is estimated that the study will take approximately 33 months between first subject enrolled and last subject visit.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Intervention Model: Sequential Assignment
Intervention Model Description: A dose escalation phase based on the use of a 3 + 3 design and treament of up to 6 subjects in each of three VX15/2503 dose levels; a fixed dose of avelumab will be employed. Once the recommended phase two dose is determined, subjects will receive that dose of VX15/205 combined with avelumab moving forward.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b/Study of VX15/2503 in Combination With Avelumab in Advanced Non-small Cell Lung Cancer
Actual Study Start Date : October 5, 2017
Estimated Primary Completion Date : May 1, 2020
Estimated Study Completion Date : May 1, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Avelumab

Arm Intervention/treatment
Experimental: VX15/2503 + avelumab
VX15/2503 at a concentration of 5 mg/kg to 15 mg/kg with a fixed dose of avelumab at 10 mg/kg, administered intravenously on a bi-weekly dosing cycle.
Drug: VX15/2503 + avelumab
Dose escalation will begin at 5 mg/kg of VX15/2503 and will increase up to 15 mg/kg with a constant dose of avelumab at 10 mg/kg. A recommended phase II dose of VX15/2503 will be determined and then utilized in the expansion phase with 10 mg/kg of avelumab.




Primary Outcome Measures :
  1. Dose Escalation Phase: Number of subjects with dose-limiting toxicities (DLT)s at each dose level [ Time Frame: 21 Days for Each Escalation Phase ]
    DLTs will be described and graded according to the Common Terminology Criteria Adverse Events version 4.03 (CTCAE v4.03) and according to the specific MedRA terms from immune mediated AEs

  2. Dose Expansion Phase: Frequency and type of adverse events (AE)s [ Time Frame: 2 Years ]
    Safety assessments will be performed on a regular basis using physical examination, spontaneous AE reporting, scheduled and unscheduled laboratory assessments, and other diagnostic evaluations as indicated. Adverse events will be reported using the Common Terminology Criteria Adverse Events version 4.03 (CTCAE v4.03).


Secondary Outcome Measures :
  1. Dose Expansion Phase: Objective Response (OR) [ Time Frame: 2 Years ]
    This is defined as complete response (CR) or partial response (PR) according to RECIST 1.1 from first dose until documented confirmed disease progression.

  2. Dose Expansion Phase: Duration of Response (DoR) [ Time Frame: 2 Years ]
    This is defined, for subjects with an objective response, as the time from first confirmed documented objective response (CR or PR) to the date of first confirmed documented objective progression of disease (PD) or death.

  3. Dose Expansion Phase: Progression Free Survival (PFS) [ Time Frame: 2 Years ]
    This is defined as the time from first dose to the date of the first confirmed documented objective progression of disease (PD) or death

  4. Dose Expansion Phase: Peak plasma concentration (Cmax) of VX15/2503 and avelumab [ Time Frame: 2 Years ]
    PK Parameter

  5. Dose Expansion Phase: Area under the plasma concentration versus time curve (AUC) of VX15/2503 and avelumab [ Time Frame: 2 Years ]
    PK Parameter

  6. Dose Expansion Phase: Half-life of VX15/2503 and avelumab [ Time Frame: 2 Years ]
    PK Parameter

  7. Dose Expansion Phase: Immunogenicity of VX15/2503 and avelumab as measured by frequency and titer of human anti human antibodies [ Time Frame: 2 Years ]
    Anti Drug Antibodies (ADA)

  8. Dose Expansion Phase: Receptor occupancy of VX15/2503 and avelumab as measured by a flow cytometry based saturation assay [ Time Frame: 2 Years ]
    PD Parameter

  9. Dose Expansion Phase: Cellular SEMA4D levels as measured by flow cytometry [ Time Frame: 2 Years ]
    PD Parameter

  10. Dose Expansion Phase: Total soluble SEMA4D levels as measured by ELISA [ Time Frame: 2 Years ]
    PD Parameter



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age > 18 years.
  2. Signed informed consent prior to the performance of any study-specific procedures, including fresh tumor biopsies.
  3. Histologically or cytologically proven advanced (stage IIIB/IV) NSCLC subjects who are immunotherapy naïve.
  4. Escalation Phase: Subjects may be enrolled with ≤ 2 lines of prior systemic anti-cancer therapy (but no immunotherapy). Subjects who have had no prior systemic anti-cancer therapy (i.e. first-line therapy) or declined first-line treatment are permitted in the Escalation Phase.
  5. Expansion Phase: Initially, only immunotherapy naïve subjects who have progressed on first-line cytotoxic chemotherapy or who have declined first-line treatment with cytotoxic chemotherapy will be enrolled. Subjects with no prior systemic anti cancer therapy (i.e. first line therapy) may be enrolled in a second cohort if approved by the SMC. Subjects previously treated with systemic adjuvant therapy, other than immunotherapy for recurrent advanced NSCLC, are also eligible.
  6. Measureable disease as defined by the RECIST 1.1.
  7. Availability of archival or fresh tumor specimen that is suitable for analysis. Acceptable samples must have been acquired using core needle biopsy or excisional biopsy. Samples that were acquired using fine needle aspiration are not acceptable.
  8. Tumor lesion accessible for biopsy after the start of treatment. (Note: this lesion should be separate from measurable lesions that will be used for response assessment.)
  9. ECOG performance status (PS) score 0-1.
  10. Tumors lack activating epidermal growth factor receptor (EGFR) mutations or ALK rearrangement (no EGFR or ALK testing is required if a subject has a KRAS mutation or squamous cell histology).
  11. Has adequate bone marrow, renal and hepatic function based upon laboratory tests as follows:

    • Absolute neutrophil count > 1500/µL
    • Platelet count > 100 x 103/µL
    • Hemoglobin > 9 g/dL, transfusion permitted
    • Total bilirubin < 1.5 x upper limit of normal (ULN) (or < 3 x ULN for subjects with Gilbert's syndrome)
    • Creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate calculation
    • AST < 2.5 x ULN (5.0 x ULN in the presence of liver metastasis)
    • ALT < 2.5 x ULN (5.0 x ULN in the presence of liver metastasis).
  12. Highly effective contraception (i.e., methods with a failure rate of less than 1 % per year) for both male and female subjects if the risk of conception exists (Note: The effects of the trial treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use highly effective contraception, defined in Protocol Appendix 9.3, or as stipulated in national or local guidelines. Highly effective contraception must be used for the duration of trial treatment, and at least for 60 days after stopping trial treatment or 6 months after stopping chemotherapy [or per label]. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately).
  13. Resolution of toxicity from prior anti-cancer therapy, to NCI CTCAE v4.03 Grade 0 or 1, except for alopecia. Subjects may be enrolled if their toxicity is determined to be irreversible and will not put them at undue risk from study treatment, based on the Investigator's assessment.

Exclusion Criteria:

  1. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints), such as PD-1, PD-L1, or cytotoxic T lymphocyte antigen-4.
  2. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on Investigator's judgment are acceptable.
  3. Concurrent anticancer treatment within 28 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative bone directed radiotherapy]; immune therapy, or cytokine therapy, except for erythropoietin.
  4. Major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy); or use of any investigational drug within 28 days before the start of trial treatment.
  5. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs before initiation of the trial treatment (with the exception of subjects with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, equivalent to ≤ 10 mg prednisone daily). Note: Previous or ongoing administration of systemic steroids for the management of an acute allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids will be completed in 14 days, or that the daily dose after 14 days will be ≤10 mg per day of prednisone or equivalent.
  6. Previous malignant disease other than the target malignancy to be investigated in this trial within the last 5 years (with the exception of adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and the subject was deemed to have been cured with no additional therapy required or anticipated to be required.
  7. Rapidly progressive disease.
  8. ECOG performance status score ≥ 2.
  9. Women who are pregnant or breastfeeding.
  10. History of pneumonitis or other interstitial lung disease
  11. Active or history of any autoimmune disease including colitis and inflammatory bowel disease (subjects with diabetes Type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
  12. Vaccination within 4 weeks of the first dose of avelumab and while on study is prohibited except for administration of inactivated vaccines (e.g. inactivated influenza vaccines).
  13. Significant acute or chronic infection including, among others: Known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (defined as, HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA or HBV core antibody positive alone with reflex to positive HBV DNA or positive HCV antibody with reflex to positive HCV RNA).
  14. CNS malignancy, the known presence of untreated or symptomatic CNS metastases. Subjects with treated brain metastasis must be stable and off steroids and anti-convulsants for at least 1 month prior to the start of study treatment. Subjects with suspected brain metastases at Screening should have a CT/MRI of the brain prior to study entry.
  15. A history of hypersensitivity to other humanized monoclonal antibodies.
  16. Significant cardiovascular disease (New York Heart Association Class II or greater), myocardial infarction within the 6 months prior to study entry, unstable angina, or cerebral vascular accident / stroke (< 6 months prior to enrollment), or serious uncontrolled cardiac arrhythmia requiring medication / active intervention, corrected QT interval [QTc] prolongation of > 470ms and/or prior diagnosis of congenital long QT syndrome.
  17. Legal incapacity or limited legal capacity.
  18. Current alcohol or drug abuse.
  19. Any psychiatric condition that would prohibit the understanding or rendering of informed consent.
  20. Prior organ transplantation or allogeneic bone marrow transplantation.
  21. Any uncontrolled medical condition (for example, inflammatory bowel disease, uncontrolled asthma), which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment or confound interpretation of study assessments.
  22. Inability to comply with visit schedule or other protocol requirements.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03268057


Contacts
Contact: John Parker, Ph.D. 585-271-2700 ext 195 JParker@vaccinex.com
Contact: Heather Stewart 207-487-3963 Heather.Stewart@Covance.com

Locations
United States, Arkansas
Highlands Oncology Group, PA Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: Joseph Beck, MD    479-587-1700    tbeck@hogonc.com   
Principal Investigator: Joseph Beck, MD         
United States, California
University of California Los Angeles (UCLA) Not yet recruiting
Los Angeles, California, United States, 90095
Contact: Jonathan Goldman, MD    310-633-8400    jgoldman@premiereoncology.com   
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Michael Shafique, MD    813-745-3883    Michael.Shafique@moffitt.org   
Principal Investigator: Michael Shafique, MD         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Ramaswamy Govindan, MD    314-747-7405    rgovinda@dom.wustl.edu   
United States, New York
University of Rochester Recruiting
Rochester, New York, United States, 14604
Contact: Megan Baumgart, MD    203-688-2259    megan_baumgart@umrc.rochester.edu   
United States, Oregon
Providence Portland Medical Center Recruiting
Portland, Oregon, United States, 97213
Contact: Rachel Sanborn, MD    503-215-6259    sanbornr@ohsu.edu   
Principal Investigator: Rachel Sanborn, MD         
Sponsors and Collaborators
Vaccinex Inc.
Merck KGaA/EMD Serono
Investigators
Study Director: John E Leonard, PhD Vaccinex Inc.

Additional Information:
Publications:
Responsible Party: Vaccinex Inc.
ClinicalTrials.gov Identifier: NCT03268057     History of Changes
Other Study ID Numbers: VX15/2503-04
First Posted: August 31, 2017    Key Record Dates
Last Update Posted: March 8, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Vaccinex Inc.:
Non-Small-Cell Lung
Carcinoma
Advanced
VX15/2503
Semaphorin 4D
SEMA4D
safety tolerability
pharmacokinetics
monoclonal antibody

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs