Clinical Trials /

Study of ADXS-503 With or Without Pembro in Subjects With Metastatic Non-Small Cell Lung Cancer

NCT03847519

Description:

A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with Pembrolizumab in Subjects with Metastatic Squamous or Non-Squamous Non-Small Cell Lung Cancer

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of ADXS-503 With or Without Pembro in Subjects With Metastatic Non-Small Cell Lung Cancer
  • Official Title: A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination With Pembrolizumab in Subjects With Metastatic Squamous or Non-Squamous Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: ADXS-503-101
  • NCT ID: NCT03847519

Conditions

  • Lung Cancer, Non-Small Cell
  • Metastatic Squamous Cell Carcinoma
  • Metastatic Non-Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
ADXS-503Lm immunotherapySafety Phase Part A
PembrolizumabKeytrudaSafety Phase Part B

Purpose

A Phase 1/2, Open-Label Study of ADXS-503 Alone and in Combination with Pembrolizumab in Subjects with Metastatic Squamous or Non-Squamous Non-Small Cell Lung Cancer

Detailed Description

      To evaluate the safety and tolerability of ADXS-503, administered as monotherapy in Part A
      and in combination with pembrolizumab in Part B, and to determine the maximum tolerated dose
      (MTD) or maximum administered dose (MAD). As well, to characterize the preliminary anti-tumor
      activity of ADXS-503, administered in combination with pembrolizumab in Part C, per RECIST
      v1.1.
    

Trial Arms

NameTypeDescriptionInterventions
Safety Phase Part AExperimentalEnroll subjects with metastatic squamous or non-squamous NSCLC who have become refractory or intolerant to standard therapy. ADXS-503 monotherapy will be evaluated at 2 planned escalating dose levels: Dose level 1: 1e8 CFU of ADXS-503, IV, every 3 weeks until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met. Dose level 2: 5e8 CFU of ADXS-503, IV, every 3 weeks until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met.
  • ADXS-503
Safety Phase Part BExperimentalEnroll subjects with metastatic squamous or non-squamous NSCLC. ADXS-503 will be evaluated at 2 planned escalating dose levels in combination with a fixed dose of pembrolizumab: Dose level 1: 1e8 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met. Dose level 2: 5e8 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met.
  • ADXS-503
  • Pembrolizumab
Efficacy Phase Part CExperimentalEnroll subjects with metastatic squamous or non-squamous NSCLC. 1e8 CFU of ADXS-503 + 200 mg of pembrolizumab, IV, every 3 weeks for up to 2 years or until disease progression, unacceptable toxicity, or another treatment discontinuation criterion is met.
  • ADXS-503
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Subject and/or their legally authorized representative must be capable of
             understanding the investigational nature, potential risks, and benefits of the study.
             The subject and/or their legally authorized representative must sign a written
             informed consent;

          2. Subject is ≥18 years of age upon signing the Informed Consent Form;

          3. Subject has histologically or cytologically confirmed stage IV (metastatic) squamous
             or non-squamous NSCLC

               -  Part A only:

                  ▪ Subject has received, and then progressed or been intolerant to up to 3 lines
                  of prior therapy in the metastatic setting, including approved chemotherapy,
                  targeted therapy, immunotherapy and antibody therapy, if eligible. Subjects who
                  have received >3 lines of prior therapy may be eligible for Part A, upon
                  discussion with and approval by the Sponsor.

                    -  Subjects will be eligible for Part A irrespective of PD-L1 expression.

                    -  Subjects will be eligible for Part A irrespective of EGFR or ALK mutation
                       status. However, subjects with an EGFR sensitizing mutation or ALK
                       translocation must have received and then progressed or been intolerant to
                       at least 1 prior line of approved targeted therapy to be eligible for Part
                       A.

               -  Part B only:

                    -  Subject is undergoing treatment with pembrolizumab monotherapy for
                       metastatic NSCLC

                    -  Subject's most recent tumor assessment is consistent with PD according to
                       RECIST v1.1

                    -  The Investigator has determined that PD should be confirmed within 4-8
                       weeks, and pembrolizumab treatment will continue pending PD confirmation

                    -  Subject is willing to undergo a confirmatory scan 4-8 weeks from the prior
                       scan that indicated progression on pembrolizumab

                    -  There is no evidence of rapid disease progression or clinical deterioration
                       in the subject that would preclude continuation of pembrolizumab treatment
                       pending confirmation of PD.

               -  Part C only:

                    -  Subject has received no prior systemic treatment in the metastatic setting.
                       Subjects previously treated with adjuvant or neoadjuvant therapy are
                       eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months
                       prior to the diagnosis of metastatic disease.

                    -  Subject has provided a formalin-fixed tumor sample from a biopsy of a tumor
                       lesion either at the time of or after the diagnosis of metastatic disease
                       AND from a site not previously irradiated, to assess for PD-L1 status.
                       Biopsies obtained PRIOR to the administration of any systemic therapy to
                       treat the subject's tumor (such as neoadjuvant/adjuvant therapy) will not be
                       permitted for analysis. The tissue sample must be received by the central
                       laboratory vendor prior to enrollment. Fine needle aspirates, Endobronchial
                       Ultrasound (EBUS) or cell blocks are not acceptable. Needle or excisional
                       biopsies, or resected tissue is required. If the tumor specimen is not
                       evaluable for PD-L1 expression by the central laboratory, an additional
                       tumor specimen may be submitted.

                    -  Subject's tumor has PD-L1 expression of ≥50%, as determined by
                       immunohistochemistry (IHC) at a central laboratory.

                    -  Subject's tumor does not harbour an EGFR sensitizing (activating) mutation
                       or ALK translocation. EGFR sensitizing mutations are mutations that are
                       amenable to treatment with TKIs (e.g., erlotinib, gefitinib, afatanib,
                       osimertinib). ALK translocations are amendable to treatment with TKIs such
                       as crizotinib, alectinib and ceritinib. Investigators must produce the
                       source documentation of the EGFR mutation and ALK translocation status in
                       all subjects with non-squamous histology AND for subjects in whom testing is
                       clinically indicated. If either an EGFR sensitizing mutation or ALK
                       translocation is detected, additional information regarding the mutation
                       status of the other molecule is not required. If the clinical site is unable
                       to provide the source documentation, EGFR and ALK testing should be
                       performed per institutional standard of care.

          4. Subject has measurable disease for response assessment as defined by RECIST v1.1 by
             the Investigator;

          5. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
             (see Appendix 11);

          6. Subject has a life expectancy of at least 3 months;

          7. Subject has recovered to Grade ≤1 by the National Cancer Institute Common Terminology
             Criteria for Adverse Events, Version 4.03 (NCI-CTCAE v4.03) of all clinically
             significant toxic effects of prior anti-cancer chemotherapy, immunotherapy,
             radiotherapy or surgery before entering this study, except for alopecia;

          8. Subject has no major existing comorbidities or medical conditions that would preclude
             therapy in the opinion of the Investigator;

          9. Subject has adequate organ function

         10. A female subject is eligible to participate if she is not pregnant (see Appendix 5),
             not breastfeeding, and at least one of the following conditions applies:

               1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR

               2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the
                  treatment period and for at least 120 days after the final dose of study
                  treatment;

         11. A female subject of childbearing potential must have a negative urine or serum
             pregnancy test within 72 hours prior to receiving the first dose of study treatment
             and throughout the study as defined in the SoA. If the urine test is positive or
             cannot be confirmed as negative, a serum pregnancy test will be required.

         12. A male subject is eligible if he agrees to follow the contraceptive guidance in
             Appendix 5 during the treatment period and for at least 120 days after the final dose
             of study treatment.

        Exclusion Criteria:

          1. Subject has an ongoing different primary malignancy. Exceptions include treated basal
             cell carcinoma of the skin or squamous cell carcinoma of the skin;

          2. Subject has an active autoimmune disease requiring systemic treatment within the past
             3 months, a documented history of clinically severe autoimmune disease, or a disorder
             that requires systemic corticosteroids or immunosuppressive agents. Subjects with
             vitiligo, psoriasis, alopecia or resolved childhood asthma/atopy not requiring
             systemic treatment would be an exception to this rule. Subjects with hypothyroidism
             who are stable on hormone replacement (>10 mg daily prednisone equivalent) or
             Sjögren's syndrome will not be excluded from the study;

          3. Subject has a diagnosis of primary immunodeficiency, is dependent on or has received
             systemic corticosteroid therapy (>10 mg daily prednisone equivalent) or any other form
             of immunosuppressive therapy within 14 days prior to the first dose of study
             treatment. Inhaled or topical corticosteroids, and adrenal replacement corticosteroid
             doses >10 mg daily prednisone equivalent, are permitted in the absence of active
             autoimmune disease;

          4. Subject has neuropathy (sensory or motor) ≥Grade 3 per CTCAE v4.03;

          5. Subject has had an allogeneic tissue/solid organ transplant;

          6. Subject has interstitial lung disease (ILD) OR has had a history of pneumonitis that
             has required oral or IV steroids;

          7. Subject has untreated central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (no new or enlarging brain metastases) by imaging for at least 2 weeks
             following treatment, and clinically stable with no symptoms due to CNS metastasis, and
             are not using corticosteroids for at least 14 days prior to the start of study
             treatment;

          8. Subject has a concurrent unstable or uncontrolled medical condition (e.g., active
             uncontrolled systemic infection, unstable angina, congestive heart failure,
             uncontrolled diabetes) or other chronic disease, which in the opinion of the
             Investigator could compromise the subject or the study;

          9. Subject has a known history of human immunodeficiency virus (HIV) infection (HIV 1/2
             antibodies);

         10. Subject has a known active hepatitis B (e.g., HBsAg reactive) or hepatitis C infection
             (e.g., HCV RNA [qualitative] is detected) or tuberculosis;

         11. Subject has an active infection requiring systemic therapy or is dependent on or
             currently receiving antibiotics that cannot be discontinued before dosing. (Note:
             Subjects who discontinue an antibiotic prior to dosing must wait at least 5 half-lives
             after the last dose of antibiotic before receiving any study treatment);

         12. Subject has known psychiatric or substance abuse disorder(s) that would interfere with
             cooperation with the requirements of the study;

         13. Subject has an implanted medical device that poses a high risk for bacterial
             colonization and/or that cannot be easily removed (e.g., prosthetic joints, artificial
             heart valves, pacemakers, orthopedic screws, metal plates, bone grafts, or other
             exogenous implants). NOTE: More common devices and prosthetics that include arterial
             and venous stents, dental and breast implants and venous access devices (e.g.,
             Port-a-Cath or Mediport) are permitted. Sponsor must be contacted prior to consenting
             any subject who has any other device or implant;

         14. Subject is pregnant or breastfeeding, or plans to become pregnant or to father
             children, from the Screening visit through at least 120 days after the final dose of
             study treatment;

         15. Subject has a contraindication (e.g., sensitivity/allergy) to trimethoprim/
             sulfamethoxazole and ampicillin;

         16. Subject has a contraindication to non-steroidal anti-inflammatory drugs (NSAIDs);

         17. Subject has a known allergy to any component of the study formulation(s);

         18. Subject has a history of listeriosis;

         19. Subject has any other serious or uncontrolled physical or mental condition/disease
             that, as judged by the Investigator, could place the subject at higher risk derived
             from their participation in the study, could confound results of the study, or would
             be likely to prevent compliance with the requirements of the study;

         20. Subject has received chemotherapy and/or radiation therapy (except palliative
             radiation therapy for disease-related pain) within 2 weeks of the first dose of study
             treatment;

         21. Subject has received monoclonal antibody or other biologic therapy within 5 half-lives
             or 28 days prior to the first dose of study treatment, whichever is shorter. An
             exception to this exclusion criterion will be pembrolizumab monotherapy for subjects
             enrolled in Part B;

         22. Subject has received prior treatment with an Lm-based immunotherapy;

         23. Subject is receiving or plans to receive future treatment with PI3K or TNFα
             inhibitors;

         24. Subject has received a live vaccine within 30 days prior to the first dose of study
             treatment;

         25. Subject has not recovered to baseline from AEs, with the exception of alopecia, due to
             previously administered agent(s);

         26. Subject has had major surgery within 6 weeks prior to the initiation of study
             treatment. NOTE:

             All surgical complications must have recovered to baseline or Grade ≤1 prior to the
             initiation of study therapy. Sponsor must be consulted prior to enrolling subjects on
             the study who recently had a major surgery or have a new artificial implant, and/or
             devices;

         27. Subject is currently participating in or has participated in a study of an
             investigational agent(s) within 4 weeks of the first dose of study treatment;

         28. Subject is or has an immediate family member (spouse or children) who, as
             investigational site or sponsor staff, is directly involved with this trial, unless
             prospective IRB approval (by chair or designee) is given allowing exception to this
             criterion for a specific subject;

             Exclusion Criteria for Part C only

         29. In Part C, subject has received systemic therapy for the treatment of their metastatic
             NSCLC.

             Completion of treatment with chemotherapy and/or radiation as part of
             neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6
             months prior to the diagnosis of metastatic disease;

         30. In Part C, subject has an EGFR sensitizing mutation and/or an ALK translocation;

         31. In Part C, baseline tumor specimen is not evaluable for PD-L1 expression by the
             central laboratory. If an additional tumor specimen is submitted AND evaluable for
             PD-L1 expression, the subject will be eligible to participate if PD-L1 expression is
             assessed as ≥50% by the central laboratory;

         32. In Part C, subject has received prior systemic chemotherapy, biological therapy, OR
             major surgery within 6 weeks of the first dose of study treatment; received thoracic
             radiation therapy of >30 Gy within 6 months of first dose of study treatment;

         33. In Part C, subject has received prior therapy with an anti-PD-1, anti-PD-L1,
             anti-PD-L2, anti- CD137, or anti-CTLA-4 antibody, or any other antibody or drug that
             specifically targets T cell co-stimulation or immune checkpoint pathways.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety/Tolerability of ADXS-503 monotherapy in Part A and ADXS-503 with pembrolizumab in Part B: graded per comment terminology criteria for adverse events (CTCAE) version 4.03
Time Frame:12 Months
Safety Issue:
Description:Safety Measures include: Adverse events (AEs); dose-limiting toxicities (DLTs) graded per comment terminology criteria for adverse events (CTCAE) version 4.03

Secondary Outcome Measures

Measure:Preliminary anti-tumor activity of ADXS-503 alone in Part A and ADXS-503 with Pembrolizumab in Part B
Time Frame:3 years
Safety Issue:
Description:Anti-tumor activity per RECIST v1.1
Measure:Progression-free survival (PFS) and PFS rates for subjects treated with ADXS-503 monotherapy in Part A and ADXS-503 + pembrolizumab in Part B and Part C.
Time Frame:4 years
Safety Issue:
Description:PFS and PFS rate per RECIST v1.1
Measure:Overall survival (OS) and OS rates for subjects treated with ADXS-503 monotherapy in Part A and ADXS-503 with pembrolizumab in Part B and Part C
Time Frame:4 years
Safety Issue:
Description:Overall survival and milestone OS rate
Measure:Safety/Tolerability of ADXS-503 with pembrolizumab in Part C: graded per comment terminology criteria for adverse events (CTCAE) version 4.03
Time Frame:5 years
Safety Issue:
Description:Safety Measures include: Adverse events (AEs); dose-limiting toxicities (DLTs) graded per comment terminology criteria for adverse events (CTCAE) version 4.03

Details

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

Trial Keywords

  • NSCLC Lung Cancer
  • Metastatic Squamous Non-Small Cell Lung Cancer
  • Metastatic Non-Squamous Cell Lung Cancer

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