Annual Meeting Proceedings Part 1 - American Society of Clinical ...

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
TPS2617 General Poster Session (Board #11B), Mon, 8:00 AM-12:00 PM
First-in-human phase I trial of NHS-IL12 in advanced solid tumors.
Presenting Author: Joseph W. Kim, Laboratory of Tumor Immunology and
Biology, Medical Oncology Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD
Background: NHS-IL12 is an antibody-cytokine conjugate consisting of two
heterodimers of interleukin (IL)-12, fused to a human monoclonal antibody
specific for DNA-histone H1 complex exposed in tumor necrosis. IL12 is a
proinflammatory cytokine, produced by activated phagocytes and dendritic
cells, that plays a critical role in regulating the transition from innate to
adaptive immunity. Early clinical trials of IL12 reported clinical responses
in metastatic renal cell carcinoma, Kaposi sarcoma (50–71% response
rate), T-cell lymphoma (56%), and non-Hodgkin’s lymphoma (21%).
However, systemic toxicity limited further clinical development. NHS-IL12
is designed to reduce toxicity associated with systemic administration of
IL12 by selectively targeting delivery to necrotic areas of tumors. A
fluorescence imaging study of NHS-murine (mu)-IL12 in mice with
syngeneic lung carcinoma demonstrated effective targeting by NHSmuIL12.
Immunohistochemistry studies further confirmed effective targeting
of tumors by NHS-muIL12. In another study in canines with
spontaneously occurring solid tumors, 2 of 11 subjects achieved a partial
response with a single dose. Methods: This is a phase I dose-escalation
study designed to determine the maximum tolerated dose of NHS-IL12 and
to define the biologically optimal dose and schedule based on immunologic
(pharmacodynamic) analysis of cytokines such as interferon-g, and IL-10,
at multiple times points from 4 hours up to 2 weeks following the
administration of NHS-IL12. Eligible patients (pts) include those with
evaluable or measurable solid tumors who have progressive disease on at
least one prior line of therapy. Pts with a condition associated with
significant necrosis of non-tumor bearing tissue, (e.g., ulcerative colitis),
are excluded. Modified immune-related response criteria are used to assess
response, the major features of these criteria being (a) imaging confirmation
of both progression and response at least 4 weeks after initial imaging,
and (b) no consideration of new lesions unless the total measurable tumor
burden meets the criteria for progressive disease. This trial opened to
accrual in Nov. 2011 and may enroll up to 78 pts.
TPS2619 General Poster Session (Board #11D), Mon, 8:00 AM-12:00 PM
A phase I clinical trial of autologous, anti-CD19 gene targeted T cells for
adults with B cell acute lymphoblastic leukemia (B-ALL). Presenting
Author: Marco L. Davila, Memorial Sloan-Kettering Cancer Center, New
York, NY
Background: Complete remission (CR) rates for B-ALL in adults is high
(�80%), but overall survival remains low (approximately 30%). Patients
with relapsed disease have a very poor prognosis with a median survival
measured in months. Therefore, there is a dire need for novel therapies for
adults with relapsed or minimal residual B-ALL. To this end we have
developed a novel T cell therapy for B cell malignancies using patient
derived T cells genetically modified to express the 19-28z chimeric antigen
receptor (CAR), an artificial T cell receptor specific to the CD19 antigen
expressed on most B cell tumors. Human T cells retrovirally modified to
express the 19-28z CAR successfully targets and eradicates B cell tumors
in vitro and systemic human B cell cancers in mice. We have recently
published the results of our initial Phase I clinical trial experience
(Brentjens, Rivière et al., Blood 2011) utilizing this technology in adults
with chronic lymphocytic leukemia. These results suggest clinical activity
and demonstrate a persistence of 19-28z� T cells that is inversely
associated with tumor burden. These studies suggest that 19-28z� T cells
may be particularly effective in relapsed B-ALL because these tumors
retain a degree of chemotherapy sensitivity, which will allow the infusion of
T cells after salvage chemotherapy when patients have low tumor burdens.
To our knowledge, this is the first clinical trial using autologous CD19
targeted T cells in adults with B-ALL. Methods: We are enrolling patients to
a Phase I T cell dose escalation trial (NCT01044069). Adults with CD19�
B-ALL classified as a CR, relapsed, or refractory are eligible for enrollment.
After patients are enrolled they are leukapheresed to obtain peripheral
blood T cells, which are then retrovirally transduced to express the 19-28z
CAR and expanded in our GMP gene transfer facility. Enrolled patients with
relapsed or refractory B-ALL undergo a cycle of re-induction chemotherapy
and conditioning cyclophosphamide followed by infusion of autologous
19-28z� T cells. To date, 11 patients have been enrolled and 2 patients
have been infused with 19-28z� T cells.
171s
TPS2618 General Poster Session (Board #11C), Mon, 8:00 AM-12:00 PM
Safety, pharmacokinetics, and antitumor activity of MEDI-573, an investigational
monoclonal antibody that targets IGF-I and IGF-II, in adult
patients with advanced solid tumors. Presenting Author: Paul Haluska,
Mayo Clinic, Rochester, MN
Background: MEDI-573 is an investigational dual-targeting human antibody
that neutralizes IGF-I/-II ligands and inhibits IGF-1R and insulin
receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid
receptors, MEDI-573 may achieve antitumor activity without perturbing
glucose homeostasis. Objectives of this phase 1 dose-escalation and
expansion study are to evaluate safety and determine the maximum
tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics,
pharmacodynamics, and immunogenicity of MEDI-573 in adult patients
with solid tumors. Methods: Patients with advanced solid tumors,
Karnofsky status �60, and adequate organ function were treated with
escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3
weeks (30 or 45 mg/kg q3w) using a 3�3 design. Three patients per dose
level were evaluated for safety. A biomarker-rich dose-expansion arm tested
weekly 5 or 15 mg/kg MEDI-573 in patients with advanced bladder cancer.
Results: Preliminary data are presented for 43 patients (25 M, 18 F),
median age 64 years. No dose-limiting toxicities or serious toxicity patterns
occurred at any dose level. Drug-related adverse events occurring in �10%
of patients were fatigue (28%), decreased appetite (23%), nausea (16%),
diarrhea (14%), and anemia (12%); the majority were � grade 2.
Perturbations in insulin and growth hormone were not observed. Clinically
significant changes in serum glucose were rare. The MTD was not reached
after completely enrolling patients through the highest dose, 45 mg/kg IV
q3w. Serum exposure of MEDI-573 increased with increasing dose. Full
suppression of IGF-I/-II was achieved with weekly and q3w dosing. No
neutralizing antibodies against MEDI-573 were detected. Of 43 patients, 8
(19%) had stable disease �12 weeks. The longest exposure was 21 months
in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573
demonstrated an acceptable safety profile at all doses tested. No doselimiting
toxicity or serious toxicities, including those related to glucose
homeostasis, were detected. These preliminary results support further
clinical development.
TPS2620 General Poster Session (Board #11E), Mon, 8:00 AM-12:00 PM
A phase I study of 1-methyl-D-tryptophan in combination with docetaxel in
metastatic solid tumors. Presenting Author: Erica Jackson, University of
South Florida Morsani College of Medicine, Tampa, FL
Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create
immune suppression and unresponsiveness to tumor antigens in tumorbearing
hosts. 1-methyl-D-tryptophan (1-MT), an oral inhibitor of the IDO
pathway, showed favorable toxicity profile and biologic activity in prior
studies. Remarkably, in prior animal models (MMTV-neu mice), 1-MT in
combination with chemotherapy produced 30% greater tumor regressions.
Based on this data, a phase I trial was initiated to study the synergism of
1-MT with docetaxel. The primary goal of this trial is to determine the MTD
and toxicity for the combination of docetaxel and oral 1-MT. A secondary
endpoint will be to determine the PK data and the overall response rate.
Methods: This phase I study utilizes a 3�3 design comprised of five dose
levels. Dose levels 1-4 will evaluate docetaxel 60mg/m2 IV d1 q3wks plus
1-MT at 300mg, 600mg, 1000mg, and 2000mg PO BID d1-21 respectively.
Dose level 5 is docetaxel 75mg/m2 IV d1 q3wks � 1-MT 2000mg
PO BID d1-21. Eligibility for this study includes patients with measurable
metastatic solid malignancy, no prior docetaxel for metastatic disease, age
�18, life expectancy �4 months, and adequate organ/marrow function.
Patients will be excluded if they meet any of the following criteria:
chemotherapy within the past 3 weeks, untreated brain metastases, active
autoimmune disease, or GI disease causing malabsorption. In addition, any
patients who have received prior immunotherapy such as ipilimumab are
excluded. Treatment will continue until disease progression, unacceptable
toxicity, or patient/physician discretion. Accrual to dose level 3 is complete
and dose level 4 accrual is underway. The PK of 1-MT and docetaxel will
also be characterized, using an HPLC assay. PK measurements for 1-MT
are drawn on C1D1 after a single dose of 1-MT is given and then on C1D8
after the morning dose of 1-MT is given. (Drawn at 0,1,2,4,8,12,24, and
48 hours) Because IDO is hypothesized to cause regulatory T cell
expansion, circulating Tregs will be quantified utilizing flow cytometry for
CD4�CD25� FoxP3� cells. (NCT01191216)
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