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

3016 Poster Discussion Session (Board #8), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A first-in-human phase I study of MORAb-004 (M4), a humanized
monoclonal antibody recognizing endosialin (TEM-1), in patients with solid
tumors. Presenting Author: Luis A. Diaz, Sidney Kimmel Comprehensive
Cancer Center at Johns Hopkins University, Baltimore, MD
Background: Endosialin (TEM-1) is a membrane glycoprotein on the cell
surface of activated mesenchymal cells (e.g. pericytes, fibroblasts and
mesenchymal tumor cells) and on a subset of human cancers. It is involved
in the development of tumor vasculature, stromal/tumor organization and
PDGFRb signaling. M4 is a humanized IgG monoclonal antibody which
targets TEM-1. Preclinical studies suggest that M4 may have single agent
activity via inhibition of the tumor microenvironment and by direct effects
on tumors expressing this target. Methods: A phase I dose escalation study
in patients (pts) with advanced solid tumors was conducted to evaluate the
safety, pharmacokinetic profile and preliminary efficacy of M4 administered
intravenously on a weekly schedule; final results are presented.
Results: 36 pts refractory to therapy were treated at 10 dose levels (0.0625
to 16 mg/kg administered i.v. on a weekly schedule). Drug-related adverse
events (AE) observed were primarily infusion toxicity (grade 1 and 2 fever,
chills, headache, myalgia). The MTD was determined to be 12 mg/kg. DLT
of grade 3 vomiting was observed at 16 mg/kg. Preliminary pharmacokinetic
(PK) analyses demonstrate M4 accumulation beginning at 4 mg/kg,
and that elimination mechanisms are saturable beginning at 0.25 mg/kg.
Exposure (AUC) increases in a greater than dose-proportional manner, with
the apparent t1/2 increasing proportionally with dose. Tumor shrinkage
(Minor/mixed tumor responses, mR) were seen in four pts (soft tissue
sarcoma (2), hepatocellular carcinoma, pancreatic neuroendocrine tumor).
Each mR was associated with prolonged disease stabilization in these pts
(6-14 months). A cohort (n�4) of pts with refractory colorectal carcinoma
demonstrated disease stabilization (15-24 weeks). Analysis of archival
tumor revealed TEM-1 stromal staining in all cases with tumor cell
expression noted on a subset of tumors of mesenchymal origin. Conclusions:
In this phase I study, M4 was tolerated up to 12 mg/kg (MTD) and early
signs of potential activity were observed. Expanded cohorts of 1-12 mg/kg
are ongoing to further define an optimal dose.
3018^ Poster Discussion Session (Board #10), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined
with cisplatin or carboplatin in patients with advanced solid tumors. Presenting
Author: Herlinde Dumez, Department of General Medical Oncology, University
Hospitals Leuven, Leuven, Belgium
Background: Volasertib (V) is a first in class, selective and potent cell cycle kinase
inhibitor that induces mitotic arrest and apoptosis by targeting Plk. This phase I
study evaluates dose-limiting toxicities (DLT), maximum tolerated dose (MTD),
safety and pharmacokinetics (PK) of V combined with cisplatin (Cis) or
carboplatin (Ca). Methods: Sequential cohorts of patients (pts) received a single
2h infusion of V with Cis (arm A) or Ca (arm B) every 3 wks. Cis and Ca were given
for up to 6 cycles (Cy); V was continued until progression or intolerance. MTD was
the highest dose at which �1/6 pts experienced a DLT in Cy 1. MTD cohorts were
expanded to 12 DLT-evaluable pts to further characterize safety. Results: As of
January 11 2012, 61 pts (arm A: 30; arm B: 31) were treated. Pt characteristics
were (arm A/B): median age 55/58 yrs, male 16/18 pts, ECOG PS 0: 13/14 pts,
PS 1: 17/17 pts. Tumors included (pts): non-small cell lung cancer (15);
sarcoma (8); colorectal cancer (6); melanoma (4); urothelial cancer (4); other
(24). Pts received V � Cis for a median [range] of 3.5 Cy [1-6], V � Ca for 2 Cy
[1-6] and V for 3.5 Cy [1-20] in arm A and 2 Cy [1-14] in B. PK analyses are
ongoing. MTD was reached at V 300 mg � Cis 100 mg/m2 and V 300 mg � Ca
AUC 6. Five partial responses (PR) were seen. 15/30 pts in arm A and 12/31 in B
achieved stable disease (SD) or PR. PR or SD for �6 Cy was observed in 6/30 pts
and 5/31 pts in arms A and B, respectively. Conclusions: In this phase I study, V
in combination with Cis or Ca at full single-agent doses was well tolerated.
Furthermore, several objective responses and cases of sustained SD were
observed in heavily pretreated pts with advanced solid tumors.
Dose levels N of pts DLTs in Cy 1 (n of pts)
Arm A:
V (mg)/Cis
(mg/m 2 )
Arm B:
V (mg)/Ca
(AUC)
*MTD
Developmental Therapeutics—Experimental Therapeutics
A1: 100/60 3 -
A2: 100/75 3 -
A3: 200/75 3 -
A4: 300/75 3 -
A5: 300/100* 6�6 Increased serum creatinine (1) �
fatigue (1), neutropenia (1)
A6: 350/75 6 Increased alanine transaminase (1),
neutropenia (1)
B1: 100/4 3 -
B2: 100/5 3 -
B3: 200/5 3 -
B4: 300/5 6 Thrombocytopenia with neutropenia (1)
B5: 300/6* 6�7 Thrombocytopenia (1) � (1)
B6: 350/5 3 Thrombocytopenia (1),
neutropenia with thrombocytopenia,
febrile neutropenia, fatigue,
nausea and anorexia (1)
177s
3017 Poster Discussion Session (Board #9), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I study of oral rigosertib in patients with advanced solid tumors.
Presenting Author: Daniel W. Bowles, Division of Medical Oncology,
University of Colorado Denver, Aurora, CO
Background: Rigosertib (ON 01910.Na) is a new multi-targeted inhibitor of
several kinases, including polo-like kinase 1 and PI-3 kinase, and is in
advanced trials for myelodysplastic syndrome and pancreatic cancer as an
IV agent. An oral formulation with good oral bioavailability has entered
phase 1 in patients (pts) with advanced solid tumors to determine the dose
limiting toxicities (DLT), recommended phase II dose, pharmacokinetic
(PK) profiles, and to document any antitumor activity of this compound.
Methods: Pts with histologically confirmed solid tumors refractory to
standard therapy were given escalating doses of rigosertib (70, 140, 280,
560, 700 mg) twice daily continuously. Doses were escalated until
intolerable grade 2 or grade 3/4 toxicities, at which point the previous dose
level was expanded to define the MTD. All pts were assessed for safety, PK,
PD and response. Urinary PK assessments were also performed at the MTD.
Results: 25 pts (median age� 59; median ECOG PS� 1) received a median
of 6 weeks of therapy at 5 dose levels: (70 mg n�3; 140 mg n�2 ; 280 mg
n�3; 560 mg n�10; 700 mg n�7). The DLT was dysuria at 700 mg and
led to expansion at 560 mg bid. There were no DLTs in the expansion
cohort. Grade 2/3 toxicities related to rigosertib included dysuria (5/1),
cystitis (4/0), urinary frequency (3/0), hematuria (2/1), abdominal pain
(2/0), pelvic pain (1/1), nausea (1/0), distention/bloating (1/0) and
hyponatremia (0/1). Improvements in dysuria were seen with oral hydration
and sodium bicarbonate. A confirmed PR occurred in 1 pt (HN squamous
cell ca, 42� weeks), and SD was observed in 2 pts with ovarian cancer (56
weeks, 28 weeks), and 1 pt each with pancreatic neuroendocrine (40
weeks), carcinoid (32 weeks), nasopharyngeal (24 weeks) and renal cell
(32� weeks) tumors. Preliminary PK data reveal plasma rigosertib levels
above the predicted pharmacodynamically active levels. Conclusions: The
MTD of oral rigosertib administered twice daily continuously is 560mg.
Dysuria is the dose limiting and most common toxicity and can be managed
with oral hydration and sodium bicarbonate. Antitumor activity has been
observed. Final safety and efficacy results, plasma and urinary PK relationships,
and mutational analyses from archival tissue will be presented.
3019 Poster Discussion Session (Board #11), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I study of intravenous PI3K inhibitor BAY 80-6946: Activity in
patients (pts) with advanced solid tumors and non-Hodgkin lymphoma
treated in MTD expansion cohorts. Presenting Author: Michael T. Lotze,
Hillman Cancer Center G27A, Pittsburgh , PA
Background: BAY 80-6946 (BAY) is a potent and highly selective reversible
pan-Class I PI3K inhibitor, previously reported to be tolerated as a 1-hr
infusion at a dose of 0.8 mg/kg on days 1, 8 and 15 every 28 days (MTD).
Additional pts were treated in MTD expansion cohorts to assess safety, PK,
biomarkers and clinical benefit in selected tumor types, as well as safety in
Type 2 diabetics. Methods: To date, 23 nondiabetic pts with solid tumors
and 5 with follicular lymphoma (FL) received BAY at the MTD, until disease
progression or unacceptable toxicity. Tumor types were selected for high
frequency of PIK3CA mutation, including breast cancer (BC; 16), endometrial
(3), gastric (2), GU transitional cell (1) and ovarian clear cell (1).
Partial enrichment for PIK3CA mutation was achieved by analysis of
plasma DNA. 3 diabetic pts have been enrolled, at starting dose of 0.4
mg/kg. PK was done after the 1st and 3rd doses. FDG-PET/CT scans were
done at baseline and 48 hrs after the 1st dose for pharmacodynamic
assessment. Results: Safety and tolerability assessments confirmed MTD.
There were no 1st cycle DLTs. Almost all nondiabetic pts had acute Grade
2/3 hyperglycemia (HG) following each dose; at least 10 of them received
insulin for 1-3 days post dose. Hypertension (HTN) lasting � 24 hrs was
common in pts with preexisting HTN, and manageable. 2 FL pts developed
interstitial pneumonitis (IP) after cycles 2 and 3, both responsive to
steroids. Diabetic pts tolerated 0.4 mg/kg. Tumor SUVmax consistently fell
at 48 hrs. 3 of 4 FL pts had partial response (PR) after 2 cycles, with 2
confirmed PR pts on BAY for 10� and 8� mos. 2 BC pts showed PR , 1
confirmed. PIK3CA mutation (n�7) does not appear to correlate with
response. Average T1/2 was 36 hrs. Observation of high Cmax in very obese
pts led to recommended maximum dose of 65 mg. Conclusions: BAY
induced PRs in pts with BC and FL. The acute toxicities of HG in most pts
and HTN in some are manageable, and IP has been limited to 2 lymphoma
pts and is responsive to steroids. The observed clinical activity of BAY,
along with its acceptable safety profile, provide a rationale for the ongoing
development of BAY in combination with cytotoxic and targeted agents.
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