Clinical Trials /

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

NCT03268057

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: VX15/2503 in Combination With Avelumab in Advanced Non-small Cell Lung Cancer
  • Official Title: Phase 1b/Study of VX15/2503 in Combination With Avelumab in Advanced Non-small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: VX15/2503-04
  • NCT ID: NCT03268057

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
VX15/2503 + avelumabVX15/2503 + avelumab

Purpose

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.

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 subjects diagnosed with advanced (stage IIIB/IV)
      NSCLC who have either progressed on first or second-line systemic anticancer therapy or who
      have declined treatment with first or second-line system anticancer therapy. 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 the 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 62 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 Immunotherapy naive subjects and dose expansion with up to 50
      subjects (up to 22 subjects that are Immunotherapy naive and up to 28 subjects that have
      failed on Immunotherapy). 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.
    

Trial Arms

NameTypeDescriptionInterventions
VX15/2503 + avelumabExperimentalVX15/2503 at a concentration of 5 mg/kg, 10 mg/kg or 20 mg/kg with a fixed dose of avelumab at 10 mg/kg, administered intravenously on a bi-weekly dosing cycle.
  • VX15/2503 + avelumab

Eligibility 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.
             Subjects in the Dose Escalation Phase must be immunotherapy naïve.

          4. i. Subjects in the Dose Escalation Phase must have either progressed on or declined
             standard first-line therapy. Subjects with fewer than 3 lines of prior palliative
             systemic anti-cancer therapy are eligible.

             ii. Subjects in the Dose Expansion Phase must have progressed on a minimum of 2 cycles
             of standard of care platinum-based chemotherapy with or without immunotherapy,
             standard of care immunotherapy without chemotherapy or must have declined standard of
             care first-line treatment options. Subjects with fewer than 3 lines of prior
             palliative systemic anti-cancer therapy are eligible.

          5. Subjects previously treated with systemic adjuvant/neoadjuvant therapy, other than
             immunotherapy are also eligible for the Dose Escalation Phase. Subjects previously
             treated with standard of care systemic adjuvant/neoadjuvant therapy are also eligible
             for the Dose Expansion Phase.

          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. Left ventricular ejection fraction > 50%

         11. Tumors lack activating epidermal growth factor receptor (EGFR) mutations, ROS-1, or
             ALK rearrangement (no EGFR or ALK testing is required if a subject has a KRAS mutation
             or squamous cell histology)..

         12. 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).

         13. 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).

        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 in the Dose
             Escalation Phase only.

          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 disease (i.e. disease progression before or at the time of
             first tumor assessment, 8 - 12 weeks after initiation of systemic anti-cancer
             therapy).

          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. Central nervous system 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation Phase: Number of subjects with dose-limiting toxicities (DLT)s at each dose level
Time Frame:21 Days for Each Escalation Phase
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Dose Expansion Phase: Objective Response (OR)
Time Frame:2 Years
Safety Issue:
Description:This is defined as complete response (CR) or partial response (PR) according to RECIST 1.1 from first dose until documented confirmed disease progression.
Measure:Dose Expansion Phase: Duration of Response (DoR)
Time Frame:2 Years
Safety Issue:
Description: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.
Measure:Dose Expansion Phase: Progression Free Survival (PFS)
Time Frame:2 Years
Safety Issue:
Description:This is defined as the time from first dose to the date of the first confirmed documented objective progression of disease (PD) or death
Measure:Dose Expansion Phase: Peak plasma concentration (Cmax) of VX15/2503 and avelumab
Time Frame:2 Years
Safety Issue:
Description:PK Parameter
Measure:Dose Expansion Phase: Area under the plasma concentration versus time curve (AUC) of VX15/2503 and avelumab
Time Frame:2 Years
Safety Issue:
Description:PK Parameter
Measure:Dose Expansion Phase: Half-life of VX15/2503 and avelumab
Time Frame:2 Years
Safety Issue:
Description:PK Parameter
Measure:Dose Expansion Phase: Immunogenicity of VX15/2503 and avelumab as measured by frequency and titer of human anti human antibodies
Time Frame:2 Years
Safety Issue:
Description:Anti Drug Antibodies (ADA)
Measure:Dose Expansion Phase: Receptor occupancy of VX15/2503 and avelumab as measured by a flow cytometry based saturation assay
Time Frame:2 Years
Safety Issue:
Description:PD Parameter
Measure:Dose Expansion Phase: Cellular SEMA4D levels as measured by flow cytometry
Time Frame:2 Years
Safety Issue:
Description:PD Parameter
Measure:Dose Expansion Phase: Total soluble SEMA4D levels as measured by ELISA
Time Frame:2 Years
Safety Issue:
Description:PD Parameter

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Vaccinex Inc.

Trial Keywords

  • Non-Small-Cell Lung
  • Carcinoma
  • Advanced
  • VX15/2503
  • Semaphorin 4D
  • SEMA4D
  • safety tolerability
  • pharmacokinetics
  • monoclonal antibody
  • IO Failure
  • Immunotherapy Failure
  • Decline Chemo

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