the safety and efficacy of namodenoson in the second-line ...€¦ · 13th ilca annual conference...

13th ILCA Annual Conference

20 ► 22 September 2019 │Chicago, USA

13th Annual Conference20 ► 22 September 2019

Chicago, USA

The Safety and Efficacy of Namodenoson in the Second-Line Treatment of Advanced Hepatocellular Carcinoma (HCC) Patients with Underlying Child-Pugh B (CPB) Liver Cirrhosis: A Phase 2 , Randomized, Double-Blind, Placebo-Controlled Trial

Salomon M. Stemmer1, Nebojsa S. Manojlovic2, Mihai Vasile Marinca3, Petar Petrov4, Nelly Cherciu5, Doina Ganea6, Tudor-Eliade Ciuleanu7, Ioana Adriana Puscas8, Muhammad Shaalan Beg9, William T. Purcell10, Adina-Emilia Croitoru11, Rumyana Nedyalkova Ilieva12, Sladjana Natošević13, Amedeia Lavinir Nita14, Dimitar Nikolaev Kalev15, Zivit Harpaz16, Motti Farbstein16, Michael H. Silverman16, David Bristol16, Inbal Itzhak16, Pnina Fishman16, and Josep M Llovet1

1Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2Military Medical Academy, Belgrade, Serbia; 3Institutul Regional de Oncologie Iasi – Sectia Oncologie Medical, Iasi, Romania; 4Complex Oncology Center–Plovdiv, EOOD, Plovdiv, Bulgaria; 5Clinica Onco-Life, Craiova, Romania; 6Spitalul Judetean de Urgenta Sfantul Ioan cel Nou Suceava, Suceava, Romania; 7Institute of Oncology/University of Medicine and Pharmacy, Cluj-Napoca, Romania; 8S.C. Pelican Impex S.R.L. - SecţiaOncologie Medicală, Oradea, Romania; 9The University of Texas Southwestern Medical Center, Dallas, TX; University of Colorado Comprehensive Cancer Center, Aurora, CO; 10Fundeni Clinical Hospital, Bucharest, Romania; Multiprofile Hospital for Active Treatment Central Onco Hospital OOD Department of Medical Oncology, Plovdiv, Bulgaria; 11Zdravstveni Centar Kladovo SlužbaOnkologije, Kladovo, Serbia; County Hospital Pratova, Ploiesti, Romania; 12Sveta Marina University Hospital, Varna, Bulgaria; 16Can-Fite BioPharma, Petach Tiqwa, Israel; 17Mount Sinai School of Medicine, New York University, New York, NY.



Background

• The incidence of HCC is increasing worldwide

‒Liver and intrahepatic bile duct cancer are the 5th and 7th leading causes of cancer deaths in males and females, respectively

• For the majority of HCC patients, their Child Pugh (CP) score is not in class A

• In selecting drugs to treat cirrhotic patients with HCC, there is a delicate balance due to limited liver reserve

•No systemic therapies have shown clinical benefit in CPB patients with advanced HCC, and thus this population represents an unmet medical need

2



Background (cont.)

3

•Namodenoson (CF102), is an A3AR agonist, currently in clinical development as a treatment for patients with advanced HCC and CPB cirrhosis‒The drug target, A3AR, is a Gi protein-associated cell surface receptor‒A3AR expression is high in liver tumor cells and low in adjacent normal cells

•Namodenoson demonstrated promising preliminary results in this population (as 1st and 2nd line therapy) in an open-label phase 1/2 clinical study (NCT00790218), with median OS of 8.1 months

3



Namodenoson

4

• Nucleoside derivative

• Molecular weight: 544.73 Da

• Water insoluble

• Orally bioavailable

• t1/2: 12 hours

• Very stable, hardly

metabolized in the liver

A3AR

4

Namodenoson MOA: down regulation of the Wnt and NF-kB signaling pathways

4



Study Design and Endpoints• Study type: Phase 2, double blind, randomized, placebo-controlled, international multi-

center study (NCT02128958)

• Objective: Assessing the efficacy and safety of namodenoson as 2nd-line therapy in advanced HCC and CPB cirrhosis

• Patients and treatment: Patients were randomized 2:1 to continuous treatment with oral BID 25 mg namodenoson or placebo

• Endpoints:‒Primary: OS ‒Secondary: Safety, PFS, OR, and DCR (response was assessed locally by RECIST and

centrally by mRECIST)

‒Exploratory: WBC A3AR at baseline and over time

• Statistical analysis: Log rank test was used to assess OS/PFS

55



Patient Disposition and Treatment Exposure

6

Patients screened (n=136)

Randomization (n= 78)

Excluded (n=58) Did not meet inclusion criteria (n=55)Withdrew ICF (n=2)Lost to F/U (n=1)

Randomized to placebo (n=28)Received placebo (n=28)

Randomized to namodenoson (n=50)Received namodenoson 25 mg BID (n=50)

Discontinued treatment (n= 28)Died (n= 25)Pt discontinued treatment (n=2)Lost to F/U (no F/U ICF) (n=1)

Discontinued treatment (n=48)Died (n=45)Pt discontinued treatment (n=1)Lost to F/U (no F/U ICF) (n=2)

Analysis (ITT, n= 28)Analysis (ITT, n=50)

66



Baseline Patient and Tumor Characteristics

7

Namodenoson

n=50

Placebo

n=28

Age, median (range), years 62 (24-81) 66 (41-83)

Gender, n (%)

Male 38 (76.0%) 19 (67.6%)

Female 12 (24.0%) 9 (32.1%)

Ethnicity, n (%)

White/Caucasian 48 (96.0%) 27 (96.4%)

Black/African 1 (2.0%) 0 (0.0%)

Asian 0 (0.0%) 1 (3.6%)

Other 1 (2.0%) 0 (0.0%)

Child-Pugh score, n (%)

7 34 (68.0%) 22 (78.6%)

8 7 (14.0%) 6 (21.4%)

9 9 (18.0%) 0 (0.0%)

BCLC stage, n (%)

B 10 (20.0%) 10 (37.5%)

C 40 (80.0%) 18 (64.3%)

Namodenoson

n=50

Placebo

n=28Hepatitis status, n (%)

None 13 (26.0%) 10 (35.7%)Hepatitis B 19 (38.0%) 10 (35.7%)Hepatitis C 25 (50.0%) 9 (32.1%)Hepatitis B and C 7 (14.0%) 1 (3.6%)

ECOG PS, n (%)

0 10 (20.0%) 5 (17.9%)

1 37 (74.0%) 21 (75.0%)2 3 (6.0%) 2 (7.1%)

AFP, n (%)

AFP≤400 17 (34.0%) 9 (32.1%)

AFP>400 33 (66.0%) 19 (67.9%)Prior therapy (chemoembolization) , n (%)

Yes 14 (28.0%) 6 (21.4%)

No 36 (72.0%) 22 (78.6%)

7



Results: OS and PFS (ITT, All Patients)

8

Primary endpoint was not met (no statistically significant OS difference)

OS PFS

HR=0.83P=0.47

Median, 4.1 moNamodenoson (n=50)

Median, 4.3 moPlacebo (n=28)

HR=0.86P=0.55



88



Results: OS and PFS in Patients with CPB7

9

OS PFS

HR=0.78P=0.41


Median, 4.3 moPlacebo (n=22)HR=0.89P=0.68



• Pre-planned subgroup analysis

9

Numerical but not statistically significant OS/PFS differences

9



Results: 12-Month OS by Treatment (CPB7 Patients)

10

44%

18%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Namodeneson Placebo

12

-mo

nth

su

rviv

al r

ate

(n=34) (n=22)

(15/34 pts)

(4/22 pts)

P = 0.028

1010


20 ► 22 September 2019 │Chicago, USA 11

Sex - MaleSex - Female

Neither EHS/PVTEither EHS/PVT

PVTNo PVT

EHSNo EHS

Locoregional TherapyNo Locoregional Therapy

Hepatitis C - PositiveHepatitis C - Negative

ECOG = 1ECOG = 0

AFP > 400AFP ≤ 400

Hepatitis B - PositiveHepatitis B - Negative

20 (25.6) 0.78 (0.30, 2.00)58 (74.4) 0.77 (0.42, 1.40)

38 (48.7) 0.90 (0.42, 1.89)40 (51.3) 0.67 (0.34, 1.33)

43 (55.1) 0.60 (0.29, 1.22)35 (44.9) 0.99 (0.48, 2.04)

21 (26.9) 1.21 (0.43, 3.44)57 (73.1) 0.73 (0.41, 1.30)

33 (44.0) 1.19 (0.52, 2.71)1

42 (56.0) 0.72 (0.37, 1.43)

58 (79.5) 0.69 (0.39, 1.22)3

15 (20.5) 1.99 (0.60, 6.62)

35 (48.6) 0.54 (0.25, 1.16)4

37 (51.4) 0.97 (0.47, 2.01)

37 (49.3) 0.90 (0.43, 1.87)2

38 (50.7) 0.86 (0.42, 1.73)

57 (73.1) 0.92 (0.50, 1.68)21 (26.9) 0.70 (0.28, 1.74)

N (%) HR (95% CI)

Favors Namodenoson Favors Placebo

11

1 Three patients with responses of 'missing' are excluded from analysis2 Three patients with responses of 'missing' are excluded from analysis3 Five patients with ECOG=2 are excluded from analysis 4 Six patients do not have AFP values at baseline or screening visits

Results: Subgroup Analysis (OS, ITT)

• No subgroup with a statistically significant difference between the arms



Results: Response Rates

12

Best response, n (%)

Namodenoson

(n=34)*

Placebo

(n=21)*CR 0 (0%) 0 (0%)

PR 3 (9%) 0 (0%)SD 17 (50%) 10 (48%)PD 14 (41%) 11 (52%)

• DCR for namodenoson treatment was superior to that of placebo after 4/6 cycles of treatment (ITT analysis): - 4 cycles: 18.0% (9/50) vs 7.1% (2/28), P=0.013 - 6 cycles: 14.0% (7/50) vs 7.1% (2/28), P=0.038

* Patients who had at least one assessment post baseline.

1212



Results: CT Imaging

13

Jan 3, 2018Nov 28, 2016 Jan 3, 2018Nov 28, 2016

Arterial phase Venous phase

1313



Results: A3AR Expression

14

• A3AR expression level at baseline was 1.98±0.36 in comparison to 1 unit in healthy subjects

• Comparable A3AR expression levels were found in the different CPB subpopulations

• A3AR expression did not change substantially during the treatment period, demonstrating that continuous treatment with namodenoson does not result in desensitization or loss of the target

1414



Treatment-related Adverse Events

15

Grade 1-2 Grade 3

Namodenosonn=50

Placebon=28

Namodenosonn=50

Placebon=28

Any 10 (20.0%) 14 (50.0%) 1 (2.0%) 1 (3.6%)Abdominal pain 1 (2.0%) — — —Abnormal weight loss 1 (2.0%) — — —Anemia 1 (2.0%) 1 (3.6%) — 1 (3.6%)Asthenia — 3 (10.7%) — —Bronchitis — 1 (3.6%) — —Chest pain 1 (2.0%) 1 (3.6%) — —Diarrhea 1 (2.0%) 1 (3.6%) — —Dyspepsia 1 (2.0%) — — —Fatigue — — — 1 (3.6%)Hypoesthesia 1 (2.0%) — — —Hyponatremia — — 1 (2.0%) —Hypotension 1 (2.0%) — — —Nausea 2 (4.0%) 1 (3.6%) — —Peripheral Edema — 1 (3.6%) — —

Grade 1-2 Grade 3

Namodenosonn=50

Placebon=28

Namodenosonn=50

Placebon=28

Paresthesia 1 (2.0%) — — —

Pyrexia — 1 (3.6%) — —

Sinus tachycardia — 1 (3.6%) — —

Vomiting 1 (2.0%) 1 (3.6%) — —

Weight decreased 1 (2.0%) — — —

Weight increased 2 (4.0%) 2 (7.1%) — —

ALT Increased 1 (2.0%) — — —

Creatinine increased — 1 (3.6%) — —

INR abnormal — 1 (3.6%) — —

Leukopenia 1 (2.0%) — — —

Neutropenia 1 (2.0%) — — —

Thrombocytopenia 1 (2.0%) — — —

Increased TSH 1 (2.0%) 2 (7.1%) — —

Decreased T3 — 1 (3.6%) — —

15



Conclusions

• Namodenoson demonstrated a favorable safety profile in patients with advanced HCC and moderate liver dysfunction

• Although the primary endpoint was not met, the subgroup analysis showed a positive efficacy signal (OS) in patients with CPB7

• The favorable safety profile and lack of liver toxicity, together with the clinical activity observed in the CPB7 subpopulation, supports further clinical development of namodenoson

16



13th Annual Conference20 ► 22 September 2019

Chicago, USA

The Safety and Efficacy of Namodenoson in the Second Line Treatment of Advanced Hepatocellular Carcinoma (HCC) Patients with Underlying Child-Pugh B (CPB) Liver Cirrhosis: A Phase 2 , Randomized, Double-Blind, Placebo-Controlled Trial

Salomon M. Stemmer1, Nebojsa S. Manojlovic2, Mihai Vasile Marinca3, Petar Petrov4, Nelly Cherciu5, Doina Ganea6, Tudor-Eliade Ciuleanu7, Ioana Adriana Puscas8, Muhammad Shaalan Beg9, William T. Purcell10, Adina-Emilia Croitoru11, Rumyana Nedyalkova Ilieva12, Sladjana Natošević13, Amedeia Lavinir Nita14, Dimitar Nikolaev Kalev15, Zivit Harpaz16, Motti Farbstein16, Michael H. Silverman16, David Bristol16, Inbal Itzhak16, Pnina Fishman16, and Josep M Llovet1

1Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2Military Medical Academy, Belgrade, Serbia; 3Institutul Regional de Oncologie Iasi – Sectia Oncologie Medical, Iasi, Romania; 4Complex Oncology Center–Plovdiv, EOOD, Plovdiv, Bulgaria; 5Clinica Onco-Life, Craiova, Romania; 6Spitalul Judetean de Urgenta Sfantul Ioan cel Nou Suceava, Suceava, Romania; 7Institute of Oncology/University of Medicine and Pharmacy, Cluj-Napoca, Romania; 8S.C. Pelican Impex S.R.L. - SecţiaOncologie Medicală, Oradea, Romania; 9The University of Texas Southwestern Medical Center, Dallas, TX; University of Colorado Comprehensive Cancer Center, Aurora, CO; 10Fundeni Clinical Hospital, Bucharest, Romania; Multiprofile Hospital for Active Treatment Central Onco Hospital OOD Department of Medical Oncology, Plovdiv, Bulgaria; 11Zdravstveni Centar Kladovo SlužbaOnkologije, Kladovo, Serbia; County Hospital Pratova, Ploiesti, Romania; 12Sveta Marina University Hospital, Varna, Bulgaria; 16Can-Fite BioPharma, Petach Tiqwa, Israel; 17Mount Sinai School of Medicine, New York University, New York, NY.

the safety and efficacy of namodenoson in the second-line ...€¦ · 13th ilca annual conference...

Documents