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

142s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2500^ Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Pharmacodynamic assessment of INCB024360, an inhibitor of indoleamine
2,3-dioxygenase 1 (IDO1), in advanced cancer patients. Presenting
Author: Robert Charles Newton, Incyte Corporation, Wilmington, DE
Background: The ineffectiveness of the immune system to control tumor
growth is, in part, a result of immunosuppression imposed by negative
regulatory mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme
that catabolizes the first and rate-limiting step in the degradation of
the essential amino acid tryptophan (Trp) to kynurenine (Kyn), has been
shown preclinically to play an important role in tumor-mediated immunosuppression.
In cancer patients (pts), elevated IDO1 levels are associated
with poor prognosis and shortened survival in a number of tumor types.
Here we describe the pharmacodynamic (PD) assessment of INCB024360,
a novel inhibitor of IDO1. Methods: Plasma samples were obtained from
consented pts in study INCB 24360-101, a phase I dose-escalation study
in patients with advanced malignancies. Trp and Kyn levels in plasma were
determined by LC/MS/MS. IDO1 activity in activated peripheral blood cells
was also monitored. Results: Using anti-IDO1 specific antisera and archived
tumor samples, we found IDO1 expression in various human tumors,
including ovarian, colorectal, breast and prostate. Consistent with this
result, higher Kyn/Trp ratios (1.5-3.4 fold above healthy volunteers) were
detected in archived plasma samples from pts, indicative of higher IDO1
activity in cancer pts. To date, 23 pts have been treated with the selective
IDO1 inhibitor INCB024360. When plasma samples from patients were
collected pre- and post-INCB024360 treatment, significant dosedependent
reductions in plasma Kyn/Trp ratios and Kyn levels were
detected. As an additional biomarker measurement, whole blood samples
collected from pts at various times after dosing were stimulated ex vivo with
interferon-� and lipopolysaccharide to increase IDO1 activity and also
showed dose-dependent decreases in IDO activity. With the current dose
regimens and assays we have successfully achieved sustained inhibition of
�90% at a well tolerated dose of INCB024360. Conclusions: This is the
first demonstration of PD activity of an IDO1-specific inhibitor in cancer
pts. Our study also confirms that IDO1 is frequently activated in cancer pts.
The methods described will be used to establish a phase II dose.
2502 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Isolation of human anti-MICA antibody from cancer patients responding to
immunotherapies. Presenting Author: Kenneth F. May, Dana-Farber Cancer
Institute, Boston, MA
Background: Immunotherapy is a promising modality for the treatment of
cancer, and elucidating the mechanism of action is crucial to guiding
patient selection and developing future immunotherapeutic strategies.
Engagement of the immune molecule NKG2D by the cancer antigen MICA
is important for immune surveillance of many cancers. Tumors can evade
immune surveillance by shedding cell surface MICA, which leads to
dampening of anti-tumor immunity. Investigations by our laboratory revealed
that patients responding to immunotherapy can mount antibody
responses targeting MICA, which permits re-engagement of immunity.
Methods: Patients with advanced cancer treated at our institution with
immunotherapies (tumor cell vaccination, ipilimumab) were identified,
including several with long-term clinical remissions. Plasma was analyzed
for MICA reactivity to three distinct MICA alleles, and rare memory B cells
reactive to MICA were isolated using tetramerized MICA protein. Immunoglobulin
heavy and light chain variable domains were sequenced with single
cell RT-PCR to generate recombinant monoclonal antibody. Results: Plasma
from patients treated with immunotherapy revealed considerable interpatient
variation in reactivity to MICA. Patients with marked plasma
reactivity (including several with sustained clinical remissions) were
selected for isolation of rare memory B cells reactive to MICA. From these
cells, we have generated a recombinant fully-human MICA-reactive monoclonal
antibody that exhibits binding to a variety of MICA alleles. Conclusions:
We have developed novel methods to analyze anti-MICA antibody responses
and isolate rare memory B cells from cancer patients who gained significant
clinical benefit from immunotherapy. This has facilitated the generation of
fully human recombinant anti-MICA monoclonal antibody. To our knowledge,
this is the first example of a specific antibody reactive to a cancer
antigen isolated from a cancer patient responding to immunotherapy. As
these antibody responses likely played a role in tumor destruction, these
results inform the development of new antibody-based immunotherapies
targeting the NKG2D-MICA pathway.
2501 Oral Abstract Session, Mon, 3:00 PM-6:00 PM
A phase I study of 1-methyl-D-tryptophan in patients with advanced
malignancies. Presenting Author: Hatem Hussein Soliman, H. Lee Moffitt
Cancer Center & Research Institute, 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) is an oral inhibitor of the IDO
pathway, currently in development as an immune adjuvant for anti-tumor
vaccines and chemotherapy. The primary goal of this trial is to determine
the MTD and toxicity for oral 1-MT. Secondary endpoints include response
rates, PK, serum tryptophan catabolites, circulating T-reg cells, and C
reactive protein (CRP) levels. Methods: This phase I study utilizes a 3�3
design comprised of ten dose levels (200, 300,400,600,800,mg QD, 600,
800,1200,1600,2000mg BID). Inclusion criteria: patients with measurable
metastatic solid malignancy, age �18, life expectancy �4 months,
and adequate organ/marrow function. Exclusion criteria: chemotherapy in
the past 3 weeks, untreated brain metastases, active autoimmune disease,
or malabsorptive GI disease. Continuous toxicity monitoring early stopping
rules were used. Results: At submission, 48 out of the planned 50 patients
were accrued. MTD was not reached at 2000mg BID. At 200mg QD dose, 3
patients previously treated with active immunotherapy (ipilimumab, n�2,
CD40-mAb, n�1) developed an autoimmune hypophysitis. Since IDO is
closely linked to both CTLA-4 and CD40/CD40L pathways this was
considered on-target effect. Subsequently, patients with prior immunotherapy
were excluded and no additional treatment related G3-5 adverse
events were observed. Five patients showed SD�6 months (2 melanoma, 2
sarcoma 1 colon) as well as some mixed responses were seen in some
patients including regression of a liver visceral metastases. 1-MT plasma
PK AUC and Cmax were proportional with dose. Cmax (~40 �M at 2000mg
BID) is at 2.9 hours and the t1/2 is at 10 hours. Elevations in CRP levels
and declines in T-reg cell counts were seen across multiple dose levels.
Additional correlative data analysis is ongoing. Conclusions: The treatment
was well tolerated and orally bioavailable. Biologic activity in terms of
prolonged disease stabilization, induction of hypophysitis, and changes in
T-reg levels and CRP were observed. Trials combining 1-MT with docetaxel
and a dendritic cell vaccine are ongoing.
2503^ Oral Abstract Session, Mon, 3:00 PM-6:00 PM
Durability of complete remission by moxetumomab pasudotox (HA22 or
CAT-8015) assessed by clone-specific real-time quantitative PCR (RQ-
PCR). Presenting Author: Robert J. Kreitman, Laboratory of Molecular
Biology, NCI, NIH, Bethesda, MD
Background: The anti-CD22 recombinant immunotoxin moxetumomab
pasudotox, also known as HA22 or CAT-8015, was recently reported in
phase I testing to achieve complete remissions (CRs) in 13 (46%) of 28
patients with relapsed/refractory hairy cell leukemia (HCL); 3 of 13
patients have relapsed. Methods: To complete this trial, 20 additional
patients received the highest dose level (50 �g/Kg every other day x 3
doses); none of the 48 HCL patients had dose-limiting toxicity (DLT).
Results: Of the first 42 patients with �6 mo of follow up off-treatment, 23
(55%) had CRs, with an overall response rate of 88%. Of the 23 CRs, 21
were evaluable for minimal residual disease (MRD) using flow cytometry of
blood and immunohistochemistry of the bone marrow biopsy, and 17
(81%) were negative. Of these 17 patients, 11 (65%) were negative by
bone marrow aspirate (BMA) flow cytometry. PCR using consensus primers
for the heavy chain immunoglobulin (IgH) rearrangement was less specific
than flow cytometry of blood, since IgH rearrangements of normal B cells,
which recovered rapidly after immunotoxin treatment, were also amplified.
For better MRD detection in blood, patient IgH sequences were cloned and
sequence specific primers and probes designed for real-time quantitative
PCR (RQ-PCR). RQ-PCR of blood was negative in 6 (100%) of 6 patients
achieving flow-negativity in both blood and BMA and positive in 3 (100%)
of 3 patients flow-negative in blood but not BMA (p�0.01). No relapses
from CR have been observed in 10 patients who became RQ-PCR-negative
in blood or flow-negative in BMA, with 5-38 (median 11) mo of follow-up.
Conclusions: We conclude that clone-specific RQ-PCR is the most sensitive
blood test for MRD in our HCL patients after moxetumomab pasudotox, and
could be used to assess the possibility of long-term molecular remissions.
We believe these results, including durable CRs without DLT, support a
pivotal trial in which moxetumomab pasudotox is compared with alternative
therapy. Note: this summary contains investigator reported data. This study
was funded by MedImmune, LLC, and supported by NCI’s Intramural
Research Program and the Hairy Cell Leukemia Research Foundation.
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