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

Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2577 General Poster Session (Board #6B), Mon, 8:00 AM-12:00 PM
Vaccine therapy with tumor-specific mutated ras peptides and IL-2,
GM-CSF, or both in adult patients with solid tumors. Presenting Author:
Osama E. Rahma, National Institutes of Health/National Cancer Institute,
Bethesda, MD
Background: We have shown in previous trials that vaccination with mutant
ras peptides corresponding to the tumor mutation is feasible and can
induce specific immune responses against the mutant proteins. Immune
adjuvants are used to enhance the effect of antigen vaccines. Here, we
tested the ras vaccine in combination with Interleukin-2 (IL-2), GM-CSF, or
the combination of both in patients with advanced malignancies. Methods:
We treated 53 patients with advanced cancers (38 CRC, 11 pancreatic, 3
NSCLC and 1 cholangiocarcinoma) with 5000�g of the corresponding
mutant ras peptide given SQ along with IL-2 (Arm A), GM-CSF (Arm B) or
both (Arm C). IL-2 was given SQ at 6.0 million IU/m2/day starting day 5, 5
days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 �g/day one
day prior to each vaccination for 4 days. Vaccines were repeated every 4
weeks for a maximum of 15 cycles or until disease progression. Results: The
median PFS and OS for the full cohort was 3.6, and 16.9, respectively.
Median PFS was 3.9, 3.2 and 3.6 months for arm A, B, C, respectively.
Median OS was 17.3, 20.8 and 9.1 months, respectively. There was no
difference in PFS or OS between the three arms (p� 0.74 and 0.99,
respectively). In a subgroup analysis, patients with advanced CRC had a
median PFS and OS of 3.5 and 14.2 months, respectively. Most adverse
events were grade I-II toxicities and resolved spontaneously. Conclusions:
Two important conclusions came out of this trial: 1) no difference was
found in clinical response between the three arms; and 2) although patients
with CRC in the subgroup analysis progressed earlier compared to historical
control (3.5 vs. 7.3 months), the time from progression to death “post
progression survival, PPS” was notably longer (10.3 vs. 5.6 months). This
provides further evidence to the emerging understanding of the difference
in clinical trial monitoring between immunotherapy and other types of
therapy. Accordingly, removing patients with standard CTEP definition of
progressive disease may adversely affect the clinical outcome of vaccine
therapy. We believe that future clinical trial design strategies in cancer
vaccine should be modified to allow patients to continue therapy despite of
disease progression.
2579 General Poster Session (Board #6D), Mon, 8:00 AM-12:00 PM
Targeting hyaluronan (HA) in tumor stroma: A phase I study to evaluate the
safety, pharmacokinetics (PK), and pharmacodynamics (PD) of pegylated
hyaluronidase (PEGPH20) in patients with solid tumors. Presenting Author:
Mitesh J. Borad, Mayo Clinic, Scottsdale, AZ
Background: HA, a glycosaminoglycan, accumulates in ~25% of solid
tumors and is associated with poor prognosis. Tumors that accumulate HA
develop high interstitial fluid pressure (IFP) and become resistant to
chemotherapy. In animal models, PEGPH20 reduced tumor-associated HA
and increased efficacy of chemotherapy. Methods: This ongoing phase 1
study was designed to assess safety, tolerability, PK, PD, and the maximum
tolerated dose (MTD) of PEGPH20 as a single agent in patients with
treatment-refractory solid tumors. IV PEGPH20 was administered in a
twice weekly or a once weekly dosing schedule with oral dexamethasone
(dex) pre-and post dose. Biomarkers included tumor histochemistry to
detect HA depletion, plasma HA catabolites, and DCE-MRI or FDG-PET.
Results: Fifteen patients have been enrolled into the study. Dose administration
ranged from 0.5 �g/kg to 5 �g/kg. Musculoskeletal events (MSEs) were
the most common and dose limiting toxicities. To date, up to 3 �g/kg twice
weekly IV infusions of PEGPH20 were well tolerated with manageable
Grade 1 MSEs in most patients. MTD has not been reached. Plasma
concentrations of PEGPH20 showed dose proportional exposure with a
terminal half life of ~2 days. Enzymatic activity of PEGPH20 was reflected
by dose-dependent HA catabolites in plasma. Pre- and post-dose tumor
biopsies from 2 colon patients demonstrated 23-60% reduction in tumor
HA after 4 weeks of dosing. Serial DCE-MRI and FDG-PET demonstrated
increased tumor perfusion (Ktrans ) and decreased metabolic activity 8 and
24hrs post-PEGPH20 in one patient each. Doses of �3 �g/kg were
tolerated with intermittent Grade 1-2 MSE. Enrollment at dose levels � 3
�g/kg is ongoing. Conclusions: Repeated IV PEGPH20 infusion resulted in
dose-dependent systemic exposure and is tolerated with concomitant dex
treatment. HA catabolites in plasma demonstrated the in vivo enzymatic
activity of PEGPH20. Reduced HA in tumor biopsies and serial DCE-MRI
and FDG-PET images confirmed PD activity. Increased tumor perfusion by
PEGPH20 may enhance drug delivery to tumor. Combination studies of
PEGPH20 with cytotoxic chemotherapy are planned.
161s
2578 General Poster Session (Board #6C), Mon, 8:00 AM-12:00 PM
An alternative clinical trial design for early cancer vaccine development to
phase 3�3 design. Presenting Author: Emily Gammoh, National Institutes
of Health, Bethesda, MD
Background: Traditional phase I, “3�3 dose escalation” design, is conducted
to identify the MTD and in some cases the optimal biologic dose.
Given their unique mechanism of action and the profile of their clinical
outcome, this design may not apply to cancer vaccines. The therapeutic
cancer vaccine FDA guidance calls for an alternative early development
design. Nevertheless, whether an alternative design should be based on
“dose escalation” is still an opened question. Methods: We analyzed the
toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine
trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4
vaccine related systemic toxicities were reported in 4952 treated patients
(1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used
dose escalation reported vaccine related DLTs, both trials used bacterial
vectors. Furthermore, correlation of immunological response with dose
level showed no consistent trend. Conclusions: Our analysis suggests that in
cancer vaccines neither toxicity nor cellular immune response correlates
with dose levels. Accordingly, dose escalation is not suitable for most
cancer vaccine studies. Here, we propose a two-step alternative design for
early development of cancer vaccines. The first step is to determine and
confirm the minimum Immune-Active Dose (IAD). If a vaccine class has
been used in humans, IAD dose is chosen based on previous experience if
the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation
will be used. For a vaccine class that has not been tested or has
undetermined toxicity we recommend “One Patient Escalation Design”
(OPSD): one patient is treated per tested dose until an immune response is
induced. To confirm this activity, an expanded cohort of 7 patients will be
tested until demonstrating an additional response. This will then be used in
phase II combination therapy trial. Alternatively, IAD can be directly tested
in combination with an immune modulator in a phase II clinical trial using a
two-stage design. The first stage of the phase 2 trial can be set at 4-5
patients for a target response rate of over 50%. If no response is seen, then
the immune modulator will be escalated in the second stage.
2580 General Poster Session (Board #6E), Mon, 8:00 AM-12:00 PM
Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of
NGR-hTNF given at high doses in patients with refractory solid tumors.
Presenting Author: Paolo Andrea Zucali, Department of Oncology, Humanitas
Cancer Center, Rozzano, Italy
Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR)
peptide for selectively targeting tumor necrosis factor (TNF) to a CD13
overexpressed by tumor vasculature. Maximum tolerated dose (MTD) of
NGR-hTNF was previously established at 45 �g/m2 , when given as 1-h
infusion every 3 weeks (q3w), with dose limiting toxicities (DLT) being
grade 3 infusion-related reactions (IRRs). We explored further dose
escalation by prolonging infusion time (2-h) and using premedication
(paracetamol). Methods: DLTs were defined as drug-related grade 3/4
adverse events (AEs). PK and soluble TNF receptors (sR1-sR2) were tested
in 46 pts. The volume transfer coefficient (Ktrans ) and initial area under
gadolinium concentration (IAUGC) were assessed before and 2 hours after
dosing by dynamic contrast-enhanced magnetic resonance imaging (DCE-
MRI) in 37 pts. Results: 12 dose levels (DLs) from 60 to 325 �g/m² q3w
were evaluated. 48 pts (PS 0/1: 21/27; M/F: 37/11; median age: 61 years)
received a total of 117 cycles (range 1-6). Prior regimens ranged from 1 to
7 (median 3). No DLT occurred and MTD was not reached. Study-emergent
grade 3 and 4 AEs were reported in 12 (25%) and 5 (10%) pts,
respectively. Grade 1/2 IRRs included chills (58%) and pyrexia (56%).
Both Cmax (p�.0001) and AUC (p�.0001) increased with dose. Posttreatment
peaks of sR2 were higher than sR1 (9.6 v 4.9 ng/mL; p�.0001).
However, changes in sRs did not differ across DLs, with a plateau in
shedding kinetics. By DCE-MRI assessment, median pre- and post-first
cycle values declined from 0.15 to 0.09 min-1 for Ktrans (p�.02) and from
10.2 to 7.2 mM/L/sec for IAUGC (p �.0005). Over treatment, 28 pts
(76%) showed decreases in IAUGC (-47%, p�.0001) and Ktrans (-59%;
p�.0001) that were inversely correlated with baseline Ktrans values
(p�.0001) and NGR-hTNF Cmax (p�.03). Of 41 evaluable pts, 12 (29%)
had stable disease for a median time of 2.9 months. Survival at 1 year was
34%, with improved survival observed in pts with lower sTNF-R2 levels
(p�.01) and greater Ktrans reductions (p�.05) after 1st cycle. Conclusions:
NGR-hTNF can be safely escalated at doses higher than MTD and induces
low shedding of receptors and early antivascular effects.
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