| Eligibility |
Inclusion Criteria:
Part A
1. Subject must be at least 18 years old and must have histologically confirmed,
unresectable, locally advanced, or metastatic PD-L1-expressing solid cancer not
amenable to standard treatment, or for whom standard treatment is not available, or in
the Investigator's opinion the standard treatment would not be in the subject's best
interest. Any level of PD-L1 expression assessed by using any Food and Drug
Administration (FDA) approved PD-L1 immunohistochemistry (IHC) assay is accepted. In
addition, another PD-L1 assay may be considered acceptable if approved by the Medical
Monitor. The assessment should have been performed on the most recent available tissue
from a site of metastatic disease (if possible).
2. Subject must have evaluable or measurable disease.
Part B
3. Requirements for separate cohorts enrolled in Part B are as follows:
- Cohort 1: Histologically confirmed recurrent or metastatic NSCLC not amenable to
standard treatment, or standard treatment is not available, or in the
Investigator's opinion the standard treatment would not be in the subject's best
interest. NOTE: subjects with driver mutations are only eligible if they have
received all appropriate targeted therapies.
- Cohort 2: Histologically confirmed recurrent, resistant, or metastatic SCCHN
(oral cavity, oropharynx, hypopharynx, or larynx) not amenable to standard
treatment, or standard treatment is not available, or in the Investigator's
opinion the standard treatment would not be in the subject's best interest.
Subjects who refuse radical resection are eligible. NOTE: nasopharyngeal cancer,
squamous cell carcinoma of any other primary anatomic location in the head and
neck, subjects with SCCHN of unknown primary, and subjects with skin squamous
cell carcinoma (SCC) of the head and neck are not eligible for this arm. The
tumor must be platinum resistant or the subject ineligible for platinum therapy
due to hypersensitivity or concerns with ototoxicity.
- Cohort 3: Subjects with any other relapsed or refractory PD-L1 positive solid
tumor not amenable to standard treatment, or standard treatment is not available,
or in the Investigator's opinion the standard treatment would not be in the
subject's best interest, who received PD-1/PD-L1 treatment. Subjects with PD-L1
positive solid tumor types, for which PD-1/PD-L1 treatment is not approved, could
be enrolled at the Investigator's discretion and after discussion with the
Medical Monitor.
4. Positive PD-L1 expression as assessed by an FDA approved PD-L1 IHC assay is required.
The assessment should have been performed on the most recently available tissue and
form a site of metastatic disease (if possible). Subjects without PD-L1 measured by an
FDA-approved diagnostic must have PD-L1 expression confirmed by an FDA-approved
diagnostic on either archived tissue or a fresh biopsy. Subjects for whom PD-L1
expression has not been determined and do not have archived tissue will require a
fresh biopsy for PD-L1 determination by an FDA-approved diagnostic.
5. Subjects must be willing to have a total of 2 on trial biopsies: one at baseline and
the other within the last 2 weeks of Cycle 2. Subjects who required a fresh biopsy at
screening may utilize the screening biopsy tissue in lieu of the baseline biopsy.
6. Subject must have at least 1 measurable tumor lesion according to RECIST 1.1.
Parts A and B
7. Subject must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 or
1.
8. Prior treatment must include a CPI (i.e., PD-1 inhibitors, PD-L1 inhibitors with or
without CTLA-4 inhibitors) if there is an approved CPI for the specific cancer type.
Subjects may also have received CPIs in an investigational setting. Subjects who have
not received a CPI and where there is no approved CPI for the specific cancer type
could be enrolled at the Investigator's discretion and after discussion with the
Medical Monitor.
9. Subject must have adequate bone marrow function (NOTE: administration of blood
products and growth factors is not allowed within 2 weeks prior to screening
laboratory tests):
- absolute neutrophil count (ANC) = 1,500/µL
- platelet count = 100,000/µL
- hemoglobin = 8.0 g/dL
10. Subject must have adequate renal function, based on estimated creatinine clearance
(eCrCl) = 50 mL/min, calculated by the Cockcroft-Gault equation.
NOTE: At the Investigator's discretion, the eCrCl result < 50 mL/min may be verified
by measured creatinine clearance (mCrCl) based on the 24-hour urine collection.
Subjects with mCrCl = 50 mL/min will be eligible irrespective of the eCrCl result
calculated by the Cockcroft-Gault equation.
11. Subject must have adequate hepatic function, as determined by:
- total bilirubin (or direct bilirubin for subjects with Gilbert's disease) < 1.5 ×
upper limit of normal (ULN)
- aspartate aminotransferase (AST) = 3 × ULN (or = 5 × ULN if liver metastasis)
- alanine aminotransferase (ALT) = 3 × ULN (or = 5 × ULN if liver metastasis)
12. Subject must have adequate serum albumin (albumin = 2.5 g/dL)
13. Subjects capable of having children must have a negative highly sensitive pregnancy
test within 72 hours before the start of treatment. Subjects who are postmenopausal (>
1 year since last menstrual cycle) or permanently sterilized (e.g., bilateral tubal
occlusion, hysterectomy, bilateral salpingectomy) may be considered as not of
reproductive potential.
14. Subjects of reproductive potential must agree either to abstain continuously from
heterosexual intercourse or to use a highly effective birth control method from
signing the informed consent until 30 days after the last dose of MT-6402 for subjects
capable of bearing children and until 90 days after the last dose of MT-6402 for
subjects capable of fathering children.
Exclusion Criteria:
Part A
1. Subjects without available tissue from a site of metastatic disease or easily biopsied
lesion (biopsy sites of non significant risk, in the opinion of the Investigator) or
unwilling to consent to biopsy.
Part B
2. Subjects without easily biopsied lesions (biopsy sites of non significant risk, in the
opinion of the Investigator) or unwilling to consent to baseline and end of Cycle 2
biopsy. Patients for whom a biopsy is not feasible must be discussed with the Medical
Monitor.
3. Subjects unwilling to have baseline and on-study core biopsy (last 2 weeks of Cycle 2)
performed.
Parts A and B
4. History or current evidence of another neoplastic disease, except cervical carcinoma
in situ, superficial noninvasive bladder tumors, curatively treated Stage I to II non
melanoma skin cancer or any previous cancer curatively treated > 2 years before the
start of treatment.
5. Active autoimmune disease currently under treatment or required systemic treatment
within 2 years (replacement therapy, e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency is allowed).
Subjects who have not required systemic treatment of an auto-immune disease for at
least 2 years may be enrolled if permission is provided after discussion with the
Medical Monitor.
6. Ongoing > Grade 1 immune related toxicity caused by prior CPI therapy (i.e., PD-1
inhibitors, PD-L1 inhibitors, or CTLA-4 inhibitors). Subjects with stable
endocrinological AEs, e.g., hypothyroidism, adrenal insufficiency, hypopituitarism, or
diabetes mellitus, must have been on a stable dose of supplemental therapy for at
least 2 weeks before screening to be eligible for this study. History of repeat Grade
2 pneumonitis or carditis on previous CPI and/or Grade 3 immune related adverse event
on previous CPI treatment.
7. Evidence of active noninfectious = Grade 2 pneumonitis or current evidence of = Grade
3 other underlying pulmonary disease.
8. Received any of the following PD-L1 inhibitors within the following time periods prior
to the first dose of MT-6402: atezolizumab - 12 months; durvalumab - 7 months;
avelumab - 2 months.
9. Any concurrent cancer treatment, apart from local treatment of non-target lesions for
palliative intent (e.g., local surgery or radiotherapy).
10. Prior radiation therapy within 4 weeks before the start of study treatment. NOTE: A
lesion in a previously irradiated area can only be considered target lesion if there
has been radiographical disease progression since the end of radiation therapy.
11. Received approved or investigational treatment for the disease under study (except PD
L1 inhibitors where exclusion criterion 6 applies) within 4 weeks before the start of
treatment. For small molecules (MW < 0.9 kDa), the washout is 5 half-lives, but at
least 2 weeks.
12. Subjects who have had allogeneic tissue or solid organ transplantation.
13. Current evidence of new or growing central nervous system (CNS) metastases during
screening. Subjects with known asymptomatic CNS metastases will be eligible if they
meet all the following criteria:
1. Evidence of leptomeningeal metastasis.
2. Have stable CNS disease on the computed tomography (CT) or magnetic resonance
imaging (MRI) scan within 4 weeks before screening compared with prior neuro
imaging.
14. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
start of study treatment.
15. History or current evidence of significant cardiovascular disease before the start of
treatment, including but not limited to the following conditions:
1. Angina pectoris requiring anti-anginal medication, (chest pain: Common
Terminology Criteria for Adverse Events [CTCAE] Grade = 2)
2. Clinically significant valvular disease.
3. Myocardial infarction within 12 months prior to the start of treatment.
4. Arterial thrombosis or pulmonary embolism within 3 months before the start of
treatment.
5. History of Grade = 2 symptomatic congestive heart failure (CHF) or New York Heart
Association (NYHA) criteria Class = II.
6. Left ventricular ejection fraction (LVEF) < 55%, assessed preferably by
echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan if ECHO is not
available, within 28 days before starting study treatment.
7. High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate >
100/min at rest and upon repeated testing, significant ventricular arrhythmia
(CTCAE Grade = 2 [ventricular tachycardia], or higher-grade atrioventricular
[AV]-block [second degree AV-block Type 2 [Mobitz 2] or third-degree AV-block])
or left ventricular bundle branch block. Subjects receiving digoxin, calcium
channel blockers, or beta adrenergic blockers are eligible at the Investigator's
discretion after consultation with the Medical Monitor if the dose has been
stable for = 2 weeks before the start of treatment with MT-6402.
8. Any of the following within 3 months before the start of treatment: pericarditis
(any CTCAE Grade), pericardial effusion (CTCAE Grade = 2), non-malignant pleural
effusion (CTCAE Grade = 2) or malignant pleural effusion (CTCAE Grade = 3)
(subjects with pleural effusion that is manageable and stable > 3 months prior to
study are eligible).
9. QT interval correction for heart rate using Fridericia's formula (QTcF) = 470 ms
(average from 3 QTcF values on the triplicate 12-lead electrocardiogram [ECG]) at
screening. In subjects with right bundle branch blocks, additional corrections
will be performed to calculate the QT equivalent JT, and depending on the result
the subject may be eligible with the agreement of the Medical Monitor.
16. Current evidence of uncontrolled human immunodeficiency virus (HIV), hepatitis B virus
(HBV), or hepatitis C virus (HCV) at screening. Serology testing is not required if
seronegativity is documented in the medical history, and if there are no clinical
signs suggestive of HIV or hepatitis infections, or suspected exposure. The following
exceptions apply for subjects with positive viral serology:
1. Subjects with HIV and an undetectable viral load and CD4 + T-cell (CD4+) counts =
350 cells/mL may be enrolled, but must be taking appropriate opportunistic
infection prophylaxis, if clinically relevant.
2. Subjects with positive HBV serology are eligible if they have an undetectable
viral load and the subject will receive antiviral prophylaxis for potential HBV
reactivation per institutional guidelines.
3. Subjects with positive HCV serology are eligible if quantitative polymerase chain
reaction (PCR) for plasma HCV RNA is below the lower limit of detection.
Concurrent antiviral HCV treatment per institutional guidelines is allowed.
17. Current treatment requiring systemic steroids at doses > 10 mg/day prednisone
equivalent.
18. Subjects with a history of hypersensitivity or serious toxic reactions to kanamycin or
other aminoglycosides.
19. Subjects with unintentional weight loss > 10% of their body weight over the preceding
2 months or less before screening.
20. Subjects who are pregnant or breastfeeding.
21. History or evidence of any other clinically significant disorder, condition or disease
(with the exception of those outlined above) that, in the opinion of the Investigator
or Medical Monitor, if consulted, would pose a risk to subject safety or interfere
with the study evaluation, procedures or completion.
|
