This is a phase I/Ib study of adoptively transferred T-cell receptor gene-engineered T cells
(TCR-T) targeting tumor-specific antigens, with in vivo CD40 activation and PD-1 blockade,
for patients with incurable cancers. The study design is a safety lead-in TCR-T with
CD40/PD-1 (3+3), followed by Simon's Two-Stage expansion design, 80% power and 5% one-sided
alpha: stage-one futility assessment at n = 10; stage-two assessment at n = 22, (accrual up
to 24 to allow for potential study drop-out).
Patients will be infused with T cells engineered to express TCRs targeting one to five
tumor-specific antigens expressed by their autologous tumor. The number of T cells infused
will range from 1e9 to 1e11. Monoclonal antibodies targeting PD-1 (pembrolizumab) and CD40
(CDX-1140, Celldex Therapeutics)43 will be administered, in that order, starting within 24
hours of cell infusion and re-administered at approximately 3 week intervals. Clinic visits
will include longitudinal evaluation of toxicities and monitoring of immunological
parameters. The presence or absence of replication competent retrovirus (RCR) will be
evaluated for the first year following adoptive cell transfer, or longer, if there is
evidence of RCR.
Tumor Response assessment by RECIST 1.1 is performed every 9-12 weeks. Study treatment
continues until progression. Option repeat TCR-T infusion is allowed and in addition may
incorporate preconditioning chemotherapy using a de-intensified non-myeloablative (NMA)
regimen consisting of a single dose of gemcitabine and a single dose of either
cyclophosphamide or epirubicin, designed to elicit immunogenic cell death and transient
lymphopenia.
The primary objective of this study is to determine the safety of the adoptive transfer of
TCR-gene engineered T cells targeting TSA in combination with CD40 and PD-1 immunotherapy.
The secondary objective is to determine whether this therapy can mediate objective clinical
responses as determined by objective criteria (e.g. RECIST 1.1). The study will also
characterize the differentiation and functional state of the TCR-gene modified T cells before
and after cell therapy and monitor their persistence in the patient after treatment. Up to 24
patients will be enrolled in this study. Based on published trials treating patients with
TCR-transduced T cells, adverse events such as fever, chills, dyspnea, hypotension, fatigue,
edema, rash, and rarely acute cytokine release syndrome, may occur.
Clinical and immunological data will be analyzed which will determine whether this therapy is
safe and effective, and whether there are biomarkers or immunological signatures that
correlate to efficacy and/or lack of efficacy. This data will determine whether additional
studies are warranted.
Inclusion Criteria:
Patients with evaluable and pathologically confirmed advanced malignancy who have exhausted
curative-intent treatment options. Enrollment is intended for epithelial cancers, though
exceptions may be considered on a case-by-case basis, per discretion of study PI.
Suitable TSA for TCR-gene therapy identified in patient's cancer as confirmed by Dr. Eric
Tran.
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
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, or ≤ 5 × ULN for participants with liver metastases
- Alkaline phosphatase ≤ 2.5 × ULN, or ≤ 5 × ULN for participants with liver metastases
- 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.
Patients positive for hepatitis B core antibody (anti-HBc, total), are eligible only if HBV
DNA is non-detectable by qPCR.
Patients positive for hepatitis C virus (HCV) antibody are eligible only if HCV RNA is
non-detectable by qPCR.
Patients positive for HIV 1/2 antibodies, are eligible if ARV treatment compliant with
documented stable CD4 > 300 for at least 6 months and undetectable viral load.
Women of childbearing potential must have negative serum/urine bHCG pregnancy test ≤ 24
hours prior to start of study and with each subsequent dose of study treatment.
Ability to give informed consent and comply with the protocol.
Anticipated lifespan greater than 12 weeks.
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, see
Appendix {A}. Patients and/or partners who are surgically sterile or postmenopausal are
exempt from this requirement. Males must agree not to donate sperm for at least 90 days
after discontinuing study treatment.
Exclusion Criteria:
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.
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.
Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for
cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(e.g., hormone replacement therapy) is acceptable.
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.
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
from all radiation-related toxicities, not require corticosteroids for this purpose and not
have had radiation pneumonitis.
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.
History of organ transplant, including allogeneic stem cell transplantation.
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, interstitial lung
disease or history of, serious chronic gastrointestinal conditions associated with
diarrhea, active noninfectious pneumonitis, 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.
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.
- Adequately treated carcinoma in situ without evidence of disease.
History of leptomeningeal carcinomatosis
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.
History of active primary immunodeficiency.
Active tuberculosis infection (clinical evaluation that includes clinical history, physical
examination and radiographic findings, and TB testing in line with local practice).
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) may participate.
Brief courses of corticosteroids for prophylaxis (e.g., contrast dye allergy) or study
treatment-related standard premedication are permitted.
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.
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.
Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti-cancer therapy with the
exception of vitiligo, alopecia, and the laboratory values defined in the inclusion
criteria.
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.
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.
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).
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.
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.
Women who are pregnant, lactating or expecting to conceive, or men who father children
within the projected duration of the study.
Unable or unwilling to comply with study requirements, including returning for follow-up
visits.
