This is a Phase 1/2, open-label, dose-escalation trial of Ad MAGEA3 and MG1-MAGEA3 in
combination with pembrolizumab in patients with NSCLC (histological subtype of squamous and
non-squamous NSCLC). In Phase 1, patients who have progressed after treatment with a
platinum-based regimen and/or PD-1/PD-L1 targeted antibody therapy will be enrolled. In Phase
2, only patients who have progressed after treatment regimen containing PD-1/PD-L1 targeted
antibody therapy will be enrolled. In the Phase 1 portion of the study, MG1-MAGEA3 treatment
will be escalated in a sequential dose-escalating design. In the Phase 2 portion of the
study, MG1-MAGEA3 treatment will be at the maximum tolerated dose (MTD) or the maximum
feasible dose (MFD). The Ad-MAGEA3 and pembrolizumab dose is fixed in both the Phase 1 and
Phase 2 portions of the trial.
Phase 1 Enrollment
Cohorts 1 through 5:
Three patients will be treated at each dose level unless a dose-limiting toxicity (DLT), as
defined below, is observed. Patients will be observed for a DLT through Day 29. After
enrollment of the first patient in each cohort, 2 additional patients will be enrolled after
the initial patient reaches Day 29 without experiencing a DLT. Treatment with MG1-MAGEA3 will
proceed to the next dose level if 0 of 3 patients experiences a DLT. If one of the first 3
patients experiences a DLT, additional patients will be enrolled until a second patient
experiences a DLT (which defines the toxic dose) or until 6 total patients have been treated,
whichever comes first. If a second DLT is not experienced within that cohort, dose escalation
If 2 DLTs are observed within a cohort, enrollment into the cohort will cease and the dose
level immediately preceding that dose will be determined as the MTD.
Ad-MAGEA3 will be administered by intramuscular (IM) injection at a dose level of 2 x 1011
virus particles (VP) on Day 1. MG1-MAGEA3 will be administered by intravenous (IV) infusion
at escalating dose levels on Day 15 and Day 18. In Cohorts 1 through 5, patients will receive
pembrolizumab at a dose of 200 mg IV on Day 22, and every 3 weeks thereafter until confirmed
radiographic progression or unmanageable toxicity.
Upon determination of the MTD/MFD (safety assessment) in Cohorts 4-5, the treatment regimen
will next be optimized such that pembrolizumab will begin on Day 1 (concurrent treatment).
The Day 15 and Day 18 doses of MG1-MAGEA3 will be the doses defined as the MTD/MFD in either
Cohort 4 or5. Specifically, the regimen evaluated in Cohort 6 is as follows:
- Day 1: Patients will receive 2 x 1011 VP IM of Ad-MAGEA3 and 200 mg IV of pembrolizumab
(the Pembrolizumab will be continued every 3 weeks [Q3W]).
- Day 15: Patients will receive IV MG1-MAGEA3 at the MTD/MFD established for the first
infusion from Cohort 4 or Cohort 5.
- Day 18: Patients will receive IV MG1-MAGEA3 at the MTD/MFD established for the second
infusion from Cohort 4 or Cohort 5.
- Three patients will be treated according to the dose schedule above unless a DLT is
observed between Day 1 and Day 29, at which time three additional patients will be
enrolled onto this cohort. If 2 DLTs occur within these six patients treated in Cohort
6, this cohort will be stopped and a new Cohort will be initated again with patients
treated concurrently with pembrolizumab but with a 0.5 log lower dose of MG1-MAGEA3 than
used in Cohort 6 for the Day 15 and Day 18 doses.
Phase 2 Enrollment Phase 2 enrollment will commence upon completion of dose escalation and
determination of the MTD/MFD. In Stage 1 of the 2-Stage design, 18 evaluable patients will be
treated at the MTD/MFD (this will include patients treated at the MTD/MFD in Phase 1 who meet
Phase 2 inclusion criteria). If 1 or more patients respond, the study may continue to Stage
2, and an additional 14 evaluable patients will be enrolled for a total of 32 evaluable
A patient will be defined as being evaluable for the primary endpoint (EPPE) and included in
the Simon 2-stage study design if they are seronegative to adenovirus Type 5, the virus used
in the prime.
Preliminary data from two other Turnstone Ad/MG1-MAGEA3 trials indicates that patients
without pre-existing anti-adenovirus antibodies (seronegative) prior to treatment have a
greater likelihood of generating MAGEA3 specific T-cell responses than those that are
seropositive at baseline. Therefore, this study is designed to primarily determine the
response rate and clinical outcome for this homogenous population of Ad5 seronegative
patients whom are most likely to benefit from Ad/MG1-MAGEA3 treatment. However, there is a
small subset of seropositive patients who developed significant anti-MAGEA3 T-cell responses
after Ad/MG1-MAGEA3 treatment. In addition, the presence of Ad5 seropositivity would not be
expected to have any significant impact on the potential benefit of MG1-MAGEA3 tumor
oncolysis. Therefore, exploratory data on clinical and immune response in the Ad5
seropositive population will be conducted and the study will enroll both Ad5 seronegative and
It is anticipated that approximately half of the patients enrolled will be seronegative to
Ad5, therefore Stage 1 of the Simon 2-stage design above will enroll approximately 18
patients and Stage 2 will enroll approximately 14 patients. Total study enrollment is
projected to be between 2 and 100 patients.
Prior to each dose level increase or the initiation of Phase 2, a safety committee composed
of independent voting members and treating physician(s) will review toxicity and other
relevant data to determine suitability of dose escalation or expansion with regards to
patient safety. Interim assessments of toxicity will be conducted throughout the trial to
monitor for safety trends and identify any new or increased toxicity not previously
associated with the IPs.
In order to be eligible for participation in this trial, the patient must:
1. Have histologically or cytologically confirmed diagnosis of NSCLC (squamous or
non-squamous) with positive expression of MAGE-A3 (primary or metastatic lesion).
2. Phase 1: Have radiographic progression after treatment with at least 1 cycle of
platinum-doublet chemotherapy and/or at least one treatment of PD-1 or PD-L1 antibody
targeted therapy. Adjuvant therapy will count as a regimen if administered within 1
year before relapse.
Phase 2: Have radiographic progression during or after treatment with anti-PD-1/PD-L1
antibody. Adjuvant therapy will count as regimen if administered within 1 year before
3. Phase 1: Patients with tumors of non-squamous NSCLC histology that have a known
epidermal growth factor receptor (EGFR) mutation and/or anaplastic lymphoma kinase
(ALK) translocation can participate in the Phase 1 portion of the study if they have
failed the appropriate tyrosine kinase inhibitor (TKI) (intolerance or documented
progression of their NSCLC) and have documented progression of their NSCLC. There is
no preferred order of treatment with TKI or platinum doublet therapy. If a patient is
found to have one molecular alteration (either sensitizing EGFR mutation or ALK
translocation), then testing for the other alteration is not required.
Phase 2: Patients with the above ALK and EGFR targetable mutations will not be
eligible for treatment.
4. Have measurable disease based on RECIST v1.1 criteria as determined by the site study
team. Tumor lesions situated in a previously irradiated area are considered measurable
if progression has been demonstrated in such lesions post irradiation treatment.
5. Have at least one tumor amenable to biopsy.
6. Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Demonstrate adequate organ function:
1. White blood cell (WBC) count ≥3,000 cells/mm3
2. Absolute neutrophil count (ANC) ≥1,000 cells/mm3
3. Hemoglobin ≥8 g/dL or ≥4.96 mmol/L (correction with transfusion or
erythropoietin-based therapy allowed to meet eligibility criteria)
4. Platelet count ≥100,000 platelets/mm3 (untransfused)
5. Total bilirubin ≤1.5 x Upper Limit of Normal (ULN) OR direct bilirubin ≤ULN for
patients with total bilirubin levels >1.5 x ULN (i.e., patients with Gilberts
6. Aspartate transaminase (AST), alanine aminotransferase (ALT) ≤2.5 x ULN; ≤5.0 x
ULN if patient has liver metastases
7. Serum chemistries Sodium, Potassium, and Calcium within normal limits (WNL) or
8. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥60 mL/min for patient with
creatinine levels >1.5 institutional ULN according to Cockcroft-Gault formula
9. Serum phosphate >0.8 mmol/L (Grade 0-1)
10. International normalized ratio (INR) ≤1.5 x ULN unless patient is receiving
anticoagulant therapy as long as prothrombin time (PT) or partial prothrombin
time (PTT) is within therapeutic range of intended use of anticoagulants
11. Activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless patient is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants
12. Resting oxygen saturation on room air ≥ 90%
8. Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
9. Female patients of childbearing potential (refer to Section 11.A.2.c) must be willing
to use an adequate method of contraception as outlined in Section 11.A.2.c, starting
with Day 1 through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient.
10. Male patients of reproductive potential (Section 11.A.2.c) must agree to use an
adequate method of contraception as outlined in Section 11.A.2.c, starting with Day 1
through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient.
11. Be willing and able to provide written informed consent for the trial.
12. Be 18 years of age (or legal age of majority in the jurisdiction) on day of signing
The patient must be excluded from participating in the trial if the patient:
1. Has disease that is suitable for local therapy administered with curative intent.
2. Has had prior treatment with any MAGE-A3 vaccine immunotherapy including Ad-MAGEA3 or
3. Is currently receiving experimental therapy or has participated in a study of an
investigational agent and received study therapy or used an investigational device
within 4 weeks of the first dose of treatment.
4. Has had prior anti-cancer monoclonal antibody (mAb) therapy within 4 weeks prior to
study Day 1 or failure to recover (i.e., to ≤ Grade 1 or to baseline status) from
adverse events (AEs) due to agents administered more than 4 weeks earlier.
5. Has been intolerant of prior PD-1/PD-L1 targeted antibody therapy for which
re-treatment would expose the patient to clinically significant risk in the opinion of
the investigator (please attain sponsor permission of enrollment of any patient with
prior intolerance to anti-PD-1/PD-L1 antibody treatment).
6. Has had prior chemotherapy, or targeted small molecule therapy, or radiation therapy
within 4 weeks prior to study Day 1 or who has not recovered (i.e., to ≤ Grade 1 or to
baseline status) from AEs due to a previously administered agent.
Note: Patients with ≤Grade 2 neuropathy or having any alopecia are an exception to
this criterion and may qualify for the study.
Note: If patient received major surgery, they must be at least 4 weeks from surgery
AND have recovered adequately from the toxicity and/or complications from the surgery
prior to starting therapy.
Note: Patients receiving prior radiation must have recovered (< Grade 1) from any
acute toxicity. Patients having irreversible but not clinically significant toxicity
Note: Patients receiving prior lung radiation with a dose of >30 Gy must wait at least
8 weeks from the date of completion of the lung radiation before the first dose of
7. Has received prior treatment with vesicular stomatitis virus (VSV) based viral vector.
8. Requires use of anti-platelet or anti-coagulant therapy that cannot be safely
suspended for per protocol biopsies as per standard of care.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous
Note: Patients with previously treated brain metastases who are stable may
participate. This exception does not include carcinomatous meningitis which is
excluded regardless of clinical stability.
10. Has clinically significant tumor invasion (e.g., impeding obstruction) of a major
vascular structure (e.g., carotid artery) or other key anatomical structure (e.g.,
pulmonary airway) or clinically significant and/or rapidly accumulating ascites,
pericardial or pleural effusions.
11. Has active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
12. Has evidence of active, non-infectious pneumonitis or current radiographic evidence of
13. Has a history of interstitial lung disease.
14. Has an active infection requiring systemic therapy.
15. Has known active Hepatitis B (e.g., Hepatitis B surface antigen [HBsAg] reactive) or
Hepatitis C (e.g., HCV RNA [qualitative] is detected) virus infection.
16. Has used anti-viral medication, within 14 days of enrollment.
17. Has conditions likely to have resulted in splenic dysfunction (e.g., splenectomy,
sickle cell anemia, radiation to the spleen >20 Gy, congenital asplenism).
18. Has significant immunodeficiency due to underlying illness (e.g., known HIV/AIDS).
19. Has received immunosuppressive medication (e.g., systemic corticosteroids) within 4
weeks prior to the first dose of trial treatment.
Note: Patients must not be receiving doses of >10 mg/day of prednisone or equivalent
at the time of study entry and corticosteroids may not be used for premedication.
20. Previous solid organ or allogeneic stem cell transplant.
21. Has uncontrolled pre-existing cardiovascular conditions and/or symptomatic cardiac
22. Has >Grade 2 dyspnea and/or requirement for supplemental oxygen.
23. Has received a live vaccine within 30 days of planned start of study therapy (Note:
killed flu vaccine acceptable).
24. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.
25. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator.
26. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
27. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with Day 1 through 120 days after the last
dose of study medication (including pembrolizumab).
28. History of severe allergic anaphylactic reactions to chimeric, human or humanized
antibodies, or fusion proteins.
29. Patients with household contacts meeting any of the following criteria for study entry
unless alternate living arrangements can be made, while under contact precautions
(from the time of initial treatment with MG1-MAGEA3 until at least 7 days after the
last dose of MG1-MAGEA3):
1. Women who are pregnant or nursing an infant
2. Children <1 year old; or
3. Individuals who are severely immunocompromised (including but not limited to:
bone-marrow or organ transplant recipients; individuals with human
Immunodeficiency virus [HIV] infection; individuals receiving chronic
immunosuppressive medication such as systemic corticosteroids).
30. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or
child) who is investigational site or Sponsor staff directly involved with this trial,
unless prospective IRB approval (by chair or designee) is given allowing exception to
this criterion for a specific patient.