A Phase II Proof-of-Concept Study of Atiprimod in Patients with Advanced Low to Intermediate Grade Neuroendocrine Carcinoma

A Phase II Proof-of-Concept
Study of Atiprimod in Patients
    with Advanced Low to
     Intermediate Grade
 Neuroendocrine Carcinoma

M. Sung1, L. Kvols2, E. Wolin3, G. Jacob4,
 C. Talluto4, J.C. Torres4, A. Parta4, E.
Rodriguez4 , K. Shailubhai4, R. Shepard4
1Departments   of Medicine and Surgery, Mount Sinai School of Medicine, New York,
New York, USA. 2Department of Interdisciplinary Oncology, Neuroendocrine Cancer
Research Group, H. Lee Moffitt Cancer Center and Research Institute, University of
   South Florida, Tampa, Florida, USA. 3Samuel Oschin Comprehensive Cancer
  Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. 4Callisto
                   Pharmaceuticals, New York, New York, USA.

Background
Effective systemic therapies for carcinoid tumors are
lacking. No systemic therapy to date has been shown
to prolong survival, either overall or progression free,
and therapy remains purely palliative with no
significant reduction of the cancer burden or even
stabilization of disease

This presentation describes an interim analysis of a
phase II open label study of a novel drug, atiprimod, for
the treatment of neuroendocrine carcinoma

What is Atiprimod?
A novel drug candidate in clinical development for late-
stage cancers
A First-in-Class Azaspirane drug

               N       N

Cationic amphiphilic small-molecule, orally available.
Displays multiplicity of anti-cancer activities:
   Pro-apoptotic and
   Anti-angiogenic,
   Inhibits Akt and STAT3 signaling pathways

Study Objective
To evaluate the safety and efficacy of atiprimod
treatment in patients with low to intermediate grade
neuroendocrine carcinoma, who have progressive
disease or carcinoid symptoms not controlled with
standard octreotide treatment

Efficacy response based on:
  RECIST response of measurable tumor;
  or,
  20% decrease in carcinoid symptom frequency

Safety will be assessed primarily based on reported
adverse events

Study Design
Phase II, multi-center, open-label, single arm study
Atiprimod dosing based on a pre-defined dose de-escalation
scheme and liver function values
Treatment may continue for up to 1 year for stable or responding
patients
Two-stage statistical design
   α (type I error rate) = .09
   β (power) = .88
   p0 = 10%; p1 = 25%
   > 4/27 responders (RECIST or 20% decrease in symptom)
   needed in stage 1;
   > 7/40 responders in stages 1 and 2 needed to declare success

Inclusion & Exclusion Criteria
Key Inclusion Criteria:
  Histologically documented low to intermediate grade
  neuroendocrine carcinoma
      Both carcinoid and islet cell eligible
  Metastatic or unresectable local/regional disease that is RECIST
  measurable
  Must have either:
      RECIST progression within 6 months of enrollment; and/or,
      Carcinoid symptom(s) despite standard octreotide
  ECOG 0-2,LFT’s < Gr 1 by NCI-CTCAE v.3

Key Exclusion Criteria:
  Any concurrent anti-cancer therapies except
      Octreotide (started > 3 months prior to 1st atiprimod dose and not to
      change octreotide dose during study)
  > 2 prior chemo regimens

Study Enrollment
 ENROLLMENT: PATIENT BASELINE DEMOGRAPHICS. ALL PATIENTS EVALUABLE FOR THIS REPORT (N = 25)
              CHARACTERISTIC                       NUMBER PATIENTS             PERCENT
SEX                Male / Female                                       15 / 10                 60% / 40%
AGE, yrs           Median / Range                                   57 / 31 to 86
ETHNICITY                                  Caucasian   18                                        72%
                                    African American   1                                          4%
                                            Hispanic   5                                         20%
                                         Portuguese    1                                           4%
ECOG*              0/1/2                                     17 / 5 / 0 – 3 data pending   77.3% / 22.7% / 0%
TUMOR SITE
Carcinoid – Bowel origin                                            5 out of 25                  20%
           - Pulmonary origin                                       4 out of 25                  16%
Islet Cell Tumor                                                    3 out of 25                  12%
Other -                                                             3 out of 25                  12%
Unknown Primary Neuro-Endocrine Cancer                              10 out of 25                 40%
LIVER METASTASES                                           9 out of 25 – 16 data pending         36%
>1 CARCINOID SYMPTOM confirmed by medical history                       5/25                     20%
or physical exam
> 1 CARCINOID SYMPTOM by subject diaries                               17/25                     68%
NUMBER PRIOR THERAPIES: Median/Range                                 2 / 1 to 5
   OCTREOTIDE –                                            21 out of 22 – 3 data pending         95.4%
   ANY CHEMO –                                              5 out of 22 – 3 data pending         22.7%
   IFN –                                                    3 out of 22 – 3 data pending         13.6%
   HEPATIC EMBOLIZATION -                                  18 out of 22 – 3 data pending         81.8%
   OTHER -                                                  2 out of 22 – 3 data pending         9.1%

Results
46 patients enrolled between Nov, 2006 – Nov, 2007
25 patients had sufficient data for this analysis as of the cut-off
date (March 14, 2008).
   Efficacy reporting includes all patients for which screening
   baseline data and at least Cycle 2 RECIST measurements were
   available, or patients who had progressive disease before
   Cycle 2 at the cut off time for the analysis.
Median follow-up is 6 cycles (range 2-12 and on-going)
2 completed all 12 planned cycles of atiprimod
7 are continuing in cycles 8-12
16 are off-study:
   7 PD
   5 SAE
   2 withdrew consent
   1 non-compliance
   1 investigator decision

Tumor Measurement
     RECIST RESPONSE AND PROGRESSION EVALUATION
                  25 Patients Evaluable

BEST OVERALL RESPONSE
                 CR                          0
                 PR                          0
                 SD                    23/25 (92%)
                                 Median duration 6 cycles
                                Range 2 to 12 and on-going
                 PD                      2/25 (8%)
PROGRESSION-FREE at 6 cycles              76.4%
(approx 6 mo)                   (Kaplan-Meier; N=13 at risk)
PROGRESSION-FREE at 12 cycles              50%
(approx 12 mo)
                                (Kaplan-Meier; N=2 at risk)

Tumor Measurement
    KM Progression Free Survival Function
Estimate (—) and 95 % Confidence Interval (---)

Symptom Relief

          CARCINOID SYMPTOM RESPONSE EVALUATION
    (17/25 RECIST-evaluable patients met symptom criteria at study
             enrollment on basis of 14 day baseline diary)
Response                                                             Patients/of total (%)
Patients with > 20% decrease in avg                                         14/17 (82%)
daily frequency of at least 1 symptom
Responding symptoms*:                         Wheezing                        2 patients
                                                 Flushing                    11 patients
                                Bowel Movements*                              5 patients

*Total of 18 improved symptoms > 14 patients because some patients experienced improvement in > 1 symptom.

Symptom Relief
Some patients had dramatic reduction in symptoms
                   Example 1
                                    2.5
Average Daily # Flushing Episodes

                                              Average Daily Flushing Episodes, Patient 008
                                     2

                                    1.5

                                     1

                                    0.5

                                     0
                                          1     2       3      4     5      6     7    8     9
                                                    Treatment Cycle # (#1=Screening)

Symptom Relief
                         Some patients had dramatic reduction in symptoms
                                            Example 2

                                    7
Average # Daily Flushing Episodes

                                    6       Average Daily Flushing Episodes, Patient 033

                                    5

                                    4

                                    3

                                    2

                                    1

                                    0
                                        1    2        3         4          5        6      7
                                                 Treatment Cycle # (#1=Screening)

Side Effects

                  Results: Serious Adverse Events (SAEs)
  (All 46 enrolled and treated patients constitute the population reported for SAEs)
Total SAEs             13/46 (28.3%) unique patients have experienced 15
                       SAEs as of the data cutoff (14-March-2008)
Investigator           9 of the15 SAEs assessed as unrelated to atiprimod. 6
Causality              assessed as possibly, probably, or definitely related
Assessment
Related SAEs           6 possibly or higher related SAEs – all involved Gr 4 or
                       other AST/ ALT elevations with or without N&V; 3 also
                       had Gr 1-2 bilirubin elevations
Related SAE            All of the LFT-based SAEs have resolved; 2 patients
resolution             were able to resume atiprimod
Study                  6 patients discontinued study participation due to SAE
discontinuation
Death as SAE           2 SAEs had an outcome of death – both involved
Outcome                complicated urinary tract infections in elderly patients;
                       assessed as unrelated to atiprimod

Conclusions
Atiprimod, administered orally on a pre-defined dose de-escalation
scheme, is very well tolerated by patients with low to intermediate
grade neuroendocrine carcinoma

Disease stabilization was seen in patients who previously had
progressive disease. Potential for long term use to stabilize
disease in patients with tumor progression

In patients with sufficient data for evaluation in this on-going trial,
a high proportion are progression free; 92%, 76.4% and 50%, after
2, 6 and 12 cycles (approx 2, 6, and 12 months), respectively

82% of patients with at least 1 carcinoid symptom experienced >
20% decrease in average daily symptom frequency of at least 1
symptom; some flushing responses were complete and sustained

The most significant AEs observed are reversible AST/ALT
increases, which are manageable by regular monitoring of the
LFTs and appropriate dose management

Next Steps
This study continues to mature and atiprimod is showing very
encouraging signs of efficacy and a well-tolerated safety profile in
patients with neuroendocrine carcinoma

To date 7 patients have enrolled in an extension trial after being
stable for more than 12 months

Atiprimod could potentially be used sequentially, either alone or
combined with other agents as patients experience sequential
episodes of progressive disease

These data support moving atiprimod into a definitive, randomized
phase III trial in advanced low to intermediate grade
neuroendocrine carcinoma