| Eligibility |
Inclusion Criteria:
1. Patients 18 years and older with metastatic or locoregionally advanced epithelial
cancers, that are considered incurable.
2. Confirmation by Tran Laboratory of neoantigen-reactive TCR(s) suitable for TCR-gene
therapy.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
4. Laboratory values:
- WBC = 2000/uL
- Neutrophils = 1000/uL
- Hgb > 8.0 g/dl (patients may be transfused to reach this level)
- Platelets > 100,000 cells/mm3
- Creatinine = 2.0 mg/dL
- AST & ALT = 2.5 × ULN
- Alkaline phosphatase = 2.5 × ULN
- Total bilirubin = 2 × ULN (except patients with Gilbert's syndrome, who must have
a total bilirubin = 3.0 mg/dL). If total bilirubin is >1.5, conjugated bilirubin
must be = ULN (conjugated bilirubin only needs to be tested if total bilirubin
exceeds ULN). If there is no institutional ULN, then conjugated bilirubin must be
< 40% of total bilirubin.
5. Patients positive for hepatitis B core antibody (anti-HBc, total), are eligible only
if HBV DNA is non- detectable by qPCR.
6. Patients positive for hepatitis C virus (HCV) antibody are eligible only if HCV RNA is
non-detectable by qPCR.
7. Patients known positive for HIV 1/2 antibodies, are eligible if ARV treatment
compliant with documented stable absolute CD4 count > 300 cells/mm3 for at least 6
months and undetectable viral load.
8. Women of childbearing potential must have negative serum bHCG pregnancy test = 24
hours prior to start of study treatment.
9. Ability to give informed consent and comply with the protocol.
10. Anticipated lifespan greater than 12 weeks.
11. Men and women of childbearing potential must agree to take appropriate pregnancy
precautions during treatment and through 180 days after last dose of study treatment.
Patients and/or partners who are surgically sterile or postmenopausal (defined by 12
or more consecutive months with no menstruation, or surgically sterile) are exempt
from this requirement. Males must agree not to donate sperm for at least 90 days after
discontinuing study treatment.
Exclusion Criteria:
1. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
2. Receipt of any investigational anticancer therapy during the last 28 days or 5
half-lives, whichever is shorter, prior to the first dose of study treatment. Receipt
of any prior anti-CD40 therapy.
3. Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment,
within 21 days (6 weeks for nitrosoureas) or at least 5 half-lives (whichever is
longer) prior to the first dose of study treatment. Concurrent use of 4. hormonal
therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is
acceptable.
5. Local treatment of isolated lesions for palliative intent is acceptable (e.g., local
surgery or radiotherapy), excluding target lesions, Palliative radiation therapy cannot be
administered less than 1 week prior to the first dose of study treatment.
6. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
radiation within 4 weeks of the first dose of study drug. Participants must have recovered
(to a grade 1 or lower) from all radiation-related toxicities, not require corticosteroids
for this purpose and not have had radiation pneumonitis.
7. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of study treatment. Note: Local surgery of isolated lesions for palliative
intent is acceptable.
8. History of organ transplant, including allogeneic stem cell transplantation. 9. History
of (non-infectious) pneumonitis/interstitial lung disease or current
pneumonitis/interstitial lung disease, including grade 1 pneumonitis (asymptomatic;
clinical or diagnostic observation only; intervention not indicated).
10. Uncontrolled intercurrent illness as deemed by the investigator, including but not
limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled
hypertension, unstable angina pectoris, unstable cardiac arrhythmia, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase risk
of incurring AEs or compromise the ability of the patient to give written informed consent.
11. History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease =1 year
before the first dose of investigational product and of low potential risk for
recurrence.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
disease (per investigator discretion).
- Adequately treated carcinoma in situ without evidence of disease (per investigator
discretion) 12. History of leptomeningeal carcinomatosis 13. Has untreated central
nervous system (CNS) metastases and/or carcinomatous meningitis. Patients whose brain
metastases have been treated may participate provided they show radiographic stability
(imaging at least four weeks apart showing no evidence of intracranial progression).
In addition, any neurologic symptoms that developed either as a result of the brain
metastases or their treatment must have resolved or be stable either, without the use
of steroids, or are stable on a steroid dose of = 10mg/day of prednisone or its
equivalent and anti-seizure medications for at least 14 days prior to the start of
treatment. Patients on a stable dose of seizure medicines for epilepsy unrelated to
cancer are eligible for the trial.
14. History of active primary immunodeficiency. 15. Active tuberculosis infection
(clinical evaluation that includes clinical history, physical examination and
radiographic findings, and TB testing in line with local practice).
16. Active autoimmune disease requiring systemic immunosuppression in excess of
physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or
equivalent).:
- Autoimmune disease that is not active (in remission), but in the judgment of the
investigator could risk substantial morbidity in the event of relapse, may be grounds
for exclusion. This can include a prior history of pneumonitis or other autoimmune
sequelae of prior immunotherapy.
- Physiologic corticosteroid replacement therapy at doses > 10 mg/day of prednisone or
equivalent for adrenal or pituitary insufficiency and in the absence of active
autoimmune disease is permitted.
- Participants with asthma that requires intermittent use of bronchodilators, inhaled
steroids, or local steroid injections may participate.
- Participants using topical, ocular, intra-articular, or intranasal steroids (with
minimal systemic absorption, per investigator discretion) may participate.
17. Brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or
study treatment-related standard premedication are permitted.
18. Receipt of live attenuated vaccine within 28 days prior to the first dose of study
treatment. Note: patients should not receive live vaccine during study treatment and
up to 30 days after the last dose of study treatment.
19. Known allergy or hypersensitivity to study drug(s) or compounds of similar
biologic composition to the study drug(s), or any of the study drug excipients.
20. Any unresolved NCI CTCAE Grade =2 toxicities from prior anti-cancer therapy (see
above for radiotherapy consideration) with the exception of vitiligo or alopecia, and
per investigator discretion for laboratory values not defined in the inclusion
criteria.
21. Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Principal Investigator or one of the Co-Principal Investigators.
22. Patients with irreversible toxicity not reasonably expected to be exacerbated by
study treatment may be included only after consultation with the Principal
Investigator or one of the Co-Principal Investigators.
23. Immune-related toxicity during prior checkpoint inhibitor therapy for which
permanent discontinuation of therapy is recommended (per product label or consensus
guidelines) OR any immune-related toxicity requiring intensive or prolonged
immunosuppression to manage (with the exception of endocrinopathy that is well
controlled on replacement hormones).
24. Significant cardiovascular disease including unstable angina pectoris,
uncontrolled hypertension or arrhythmia, congestive heart failure (NYHA Class III or
IV) related to primary cardiac disease, uncontrolled ischemic or severe valvular heart
disease. Patients with a history of myocardial infarction, cerebral vascular accident,
thrombosis or pulmonary embolus within 12 months prior to the first dose of study
treatment are excluded from this study.
25. Any other acute or chronic medical or psychiatric condition or laboratory
abnormality that could increase the risk associated with trial participation or trial
drug administration or could interfere with the interpretation of trial results and,
in the judgment of the investigator, would make the patient inappropriate for entry
into the trial.
26. Women who are pregnant, lactating or expecting to conceive, or men who father
children within the projected duration of the study.
27. Unable or unwilling to comply with study requirements, including follow-up visits.
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