ANTI-VEGFR2 ANTIBODY THERAPY FOR HEPATOCELLULAR CARCINOMA

Abstract

The invention provides for a human antibody that binds to human vascular endothelial growth factor receptor 2, preferably ramucirumab, for the treatment of hepatocellular carcinoma in patients having levels of alpha-fetoprotein (AFP) of 1.5 ULN or greater, and as a predictive method for the treatment of HCC in patients having AFP levels of 1.5×ULN or greater.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

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8. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

12. (canceled)

13. An in vitro method of selecting a patient having a hepatocellular tumor for treatment with a therapeutically effective amount of ramucirumab, comprising assaying for the presence of alpha-fetoprotein in a sample taken from the patient, wherein the patient is selected for treatment with ramucirumab if alpha-fetoprotein is present in the sample at a level of 10 ng/mL or greater.

14. A method of identifying a hepatocellular tumor patient eligible for treatment with ramucirumab, comprising assaying for the presence of alpha-fetoprotein in a sample taken from the patient prior to the administration of a therapeutically effective amount of ramucirumab, wherein the patient is eligible for treatment with ramucirumab if the alpha-fetoprotein level is 10 ng/mL or greater.

15. The method according to claim 14, wherein the sample is plasma or serum.

16. (canceled)

17. The method according to claim 14, wherein the alpha-fetoprotein level is 15 ng/mL or greater.

18. The method according to claim 14, wherein the alpha-fetoprotein level is 400 ng/mL or greater.

19. A therapeutic regimen for treating a patient with a hepatocellular tumor, comprising: (1) assaying for the presence of alpha-fetoprotein in a sample taken from a patient (2) selecting the patient for treatment with ramucirumab if alpha-fetoprotein is present in the sample at a level of 10 ng/mL 1.5 times the upper limit of normal or greater, and (3) administering ramucirumab to the patient.

20. (canceled)

21. (canceled)

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24. (canceled)

25. A method of identifying a patient with a hepatocellular tumor for treatment with an anti-VEGFR2 antibody, comprising assaying the amount of alpha-fetoprotein in a sample from the patient; wherein the patient is eligible for treatment with the anti-VEGFR2 antibody if the amount of alpha-fetoprotein in the sample is 10 ng/mL or greater; wherein the anti-VEGFR2 antibody comprises two heavy chains, each with the amino acid sequence of SEQ ID NO: 1, and two light chains, each with the amino acid sequence of SEQ ID NO: 2; wherein the patient was previously treated with sorafenib.

26. The method of claim 25, wherein the alpha-fetoprotein level is 400 ng/mL or greater.

27. The method of claim 26, wherein the sample is plasma or serum.

28. The method of claim 27, wherein the anti-VEGFR2 antibody is administered at a dose of about 8 mg/kg.

Description

EXAMPLES

[0097] The following examples further illustrate the invention, but should not be construed to limit the scope of the invention in any way. Detailed descriptions of conventional methods, such as those employed in the construction of vectors and plasmids, the insertion of genes encoding polypeptides into such vectors and plasmids, the introduction of plasmids into host cells, and the expression and determination thereof of genes and gene products can be obtained from numerous publications, including Sambrook, J. et aL, Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press (1989) and Coligan, J. et al. Current Protocols in Immunology, Wiley & Sons, Incorporated (2007).

TABLE-US-00001 TABLE 1 Amino Acid Sequence of ramucirumab Heavy and Light Chain SEQ SEQ ID ID Heavy Chain NO. Light Chain NO. Full EVQLVQSGGGLV 1 DIQMTQSPSSVS 2 Length KPGGSLRLSCAA ASIGDRVTITCR SGFTFSSYSMNW ASQGIDNWLGWY VRQAPGKGLEWV QQKPGKAPKLLI SSISSSSSYIYY YDASNLDTGVPS ADSVKGRFTISR RFSGSGSGTYFT DNAKNSLYLQMN LTISSLQAEDFA SLRAEDTAVYYC VYFCQQAKAFPP ARVTDAFDIWGQ TFGGGTKVDIKR GTMVTVSSASTK TVAAPSVFIFPP GPSVLPLAPSSK SDEQLKSGTASV STSGGTAALGCL VCLLNNFYPREA VKDYFPEPVTVS KVQWKVDNALQS WNSGALTSGVHT GNSQESVTEQDS FPAVLQSSGLYS KDSTYSLSSTLT LSSVVTVPSSSL LSKADYEKHKVY GTQTYICNVNHK ACEVTHQGLSSP PSNTKVDKRVEP VTKSFNRGEC KSCDKTHTCPPC PAPELLGGPSVF LFPPKPKDTLMI SRTPEVTCVVVD VSHEDPEVKFNW YVDGVEVHNAKT KPREEQYNSTYR VVSVLTVLHQDW LNGKEYKCKVSN KALPAPIEKTIS KAKGQPREPQVY TLPPSREEMTKN QVSLTCLVKGFY PSDIAVEWESNG QPENNYKTTPPV LDSDGSFFLYSK LTVDKSRWQQGN VFSCSVMHEALH NHYTQKSLSLSP GK

[0098] A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients with Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib.

Study Design:

[0099] The Study is A Multicenter, Randomized, Double-Blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) Versus Placebo and BSC as Second-Line Treatment in Patients with Hepatocellular Carcinoma Following First-Line Therapy With Sorafenib.

[0100] Approximately 544 enrolled patients with Child-Pugh Class A score at baseline who meet all eligibility criteria are randomized into two Arms. Arm A patients receive Ramucirumab (IMC-1121B) Drug Product (DP) and Best Supportive Care (BSC) and Arm B patients receive placebo and BSC. At randomization, patients are stratified by geographic region (North America vs Europe vs East Asia), and etiology of liver disease (hepatitis B vs hepatitis C vs other etiologies). Ramucirumab DP is a sterile, preservative-free solution for infusion and is formulated in an aqueous solution at a concentration of 10 mg/mL (500 mg/50-mL vial), administered as an intravenous (I.V.) infusion at a dose of 8 mg/kg every 2 weeks. The infusion is delivered in approximately 60 minutes. The infusion rate does not exceed 25 mg/minute. Placebo drug product is a sterile, preservative-free solution for infusion containing histidine buffer only. The volume of placebo drug product administered is calculated as if it were active product formulated in an aqueous solution at a concentration of 10 mg/mL (500 mg/50-mL vial) (with a dose of 8 mg/kg). The first dose of ramucirumab DP (or placebo) is dependent upon the patient's baseline body weight in kilograms. Subsequent doses of ramucirumab DP (or placebo) must be recalculated if there is a ≧10% change (increase or decrease) in body weight from last dose calculation; subsequent doses may be recalculated if there is a <10% change (increase or decrease) in body weight from last dose calculation.

[0101] A treatment cycle is defined as 2 weeks, with radiologic evaluation every 6 weeks (±3 days) after first dose of study therapy for the first 6 months, and every 9 weeks (±3 days) thereafter. There is no planned interruption between treatment cycles. The treatment regimen is continued until radiographic progression or symptomatic deterioration characterized as progression of disease, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the patient, or investigator decision.

Efficacy Analysis:

[0102] Final analysis is performed after 438 OS events are observed in HCC patients with Child-Pugh Class A score. In addition, an interim analysis for unequivocal efficacy is performed after approximately 328 OS events; if unequivocal efficacy is declared, then this interim analysis constitutes the final inferential analysis of OS, and any subsequent analysis based on a larger number of OS events are considered exploratory.

[0103] The end of trial occurs when Study completion has occurred and the last patient has discontinued study treatment and completed the 30-Day Safety Follow-up visit (and any AEs that are serious or considered related to study treatment or that caused discontinuation of treatment are followed until the event is resolved, stabilized, returned to baseline, is deemed irreversible, or otherwise been explained).

[0104] The primary efficacy endpoint is Overall Survival (OS). The secondary efficacy endpoints are Progression-free survival (PFS), Objective response rate (ORR), Time to radiographic progression (TTP), Patient-reported outcomes (PRO) based on FHSI-8 and EQ-5D.

[0105] Tumor measurements are done by CT scan or equivalent and assessed according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1). Despite any treatment delays, the imaging studies are collected approximately every 6 weeks (±3 days) after first dose for the first 6 months, and every 9 weeks (±3 days) thereafter.

[0106] Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the patient is alive at the end of the follow-up period or is lost to follow-up, OS data is censored on the last date the patient is known to be alive. Overall survival is evaluated by the Kaplan-Meier method, and a 95% confidence interval (CI) is provided for the median OS in each treatment arm.

[0107] The primary analysis compares the observed OS between the 2 treatment arms (ramucirumab DP plus BSC versus placebo plus BSC). The primary analysis is conducted in the ITT population (patients with Child-Pugh Class A score). The comparison uses the log-rank test, stratified by randomization stratification factors: geographic region (North America vs Europe vs East Asia, where the stratification label “North America” comprises countries from North America and South America; the label “Europe” comprises countries from Europe, Israel, Australia, and New Zealand; and the label “East Asia” comprises countries from Asia, except for Israel), and etiology of liver disease (hepatitis B vs hepatitis C vs other etiologies). A sensitivity analysis may be performed using the etiology of liver disease reported on the eCRF. An additional analysis with an unstratified log-rank test is also performed. The estimation of the survival curves for the 2 treatment groups is generated using the Kaplan-Meier methodology. A stratified Cox proportional hazards regression model to compare the treatments within the clusters defined by the stratifying variables is also performed to generate the hazard ratio (HR). An additional unstratified Cox regression model is employed to explore the effects of prognostic variables, including the stratification variables and additional factors (eg, presence of macrovascular invasion, extrahepatic spread, BCLC stage, presence vs absence of histologic confirmation of diagnosis, and prior treatment with sorafenib [including duration of treatment and reasons for discontinuation]), on treatment efficacy. The primary statistical analysis is conducted in the Child-Pugh Class A population only and includes all randomized patients with Child-Pugh Class A score at baseline. Overall survival, PFS, and time to radiographic progression is evaluated by the Kaplan-Meier method with a 95% confidence interval (CI) for the median time. The primary analysis compares the OS observed with ramucirumab DP (plus BSC) versus placebo (plus BSC); the 2 arms are compared using a stratified log-rank test. ORR is presented with a 2-sided 95% CI, with best overall response (classified according to RECIST v 1.1 or similar guidelines) summarized by frequency and percentage. The ORR in each treatment group is compared using the Cochran-Mantel-Haenszel test adjusted for the stratification variables.

[0108] FHSI-8 scores and their change from baseline are summarized descriptively at each assessment time point. The change from baseline in FHSI-8 is compared to determine whether statistically significant differences exist between the ramucirumab DP and placebo arms. The EQ-5D data is scored as an index where 0=death and 1=perfect health, using the UK weighting algorithm. The visual analogue scale (VAS) are scored from 0 (worst imaginable health state) through 100 (best imaginable health state).

[0109] Survival follow-up is conducted after discontinuation of study therapy, every 2 months ±7 days for as long as the patient is alive, but not beyond study completion. (Survival follow-up is not conducted for patients on the extension period of the study.)

Results:

[0110] A total of 565 patients, who met all eligibility criteria, were randomized into the two treatment arms. The primary efficacy endpoint of OS in the ramucirumab DP arm versus placebo arm resulted in a median OS of 9.17 months (95% CI=8.05, 10.64) and 7.62 months (95% CI=6.01, 9.33) respectively. The stratified HR for this analysis was 0.866 (95% CI=0.717, 1.046) with a stratified Log-rank p-value of p=0.1391. Although the p-value did not reach statistical significance, the HR of 0.866 represents a 13% reduction in the risk of death for patients receiving ramucirumab. These results indicate a trend for improvement in survival in the ramucirumab arm compared to the placebo arm.

[0111] The median PFS in the ramucirumab DP arm and the placebo arm was 2.8 months (95% CI=2.7, 3.9) and 2.1 months (95% CI=1.6, 2.7) respectively. The stratified HR for this analysis was 0.625 (95% CI=0.522, 0.750) with a stratified Log-rank p-value of p<0.0001. The 6-month and 9-month PFS rates for the ramucirumab arm were 32.1% and 20.7%, respectively, and the 6-month and 9-month PFS rates for the placebo arm were 12.9% and 8.3%, respectively. These results demonstrate that ramucirumab has a meaningful impact on PFS, by more than doubling the PFS rates at 6 and 9 months when compared with placebo.

[0112] The time to progression (TTP) in the ramucirumab DP treatment arm and placebo treatment arm resulted in 3.48 months (95% CI=2.8, 4.5) and 2.63 months (95% CI=1.6, 2.8), respectively. The stratified HR for this analysis was 0.593 (95% CI=0.487, 0.722) with a stratified Log-rank p-value of <0.0001. The 6-month and 9-month TTP rates for the ramucirumab arm were 37.0% and 27.0%, respectively, and the 6-month and 9-month TTP rates for the placebo treatment arm were 14.9% and 10.8%, respectively. These results demonstrate that ramucirumab has a meaningful impact on TTP, more than doubling the progression-free rates at 6 and 9 months compared with placebo.

[0113] The overall response rate (complete response +partial response) in the ramucirumab arm and placebo arm was 7.1% (95% CI=4.6, 10.7) and 0.7% (95% CI=0.2, 2.5), respectively, with a p-value of <0.0001 using the Cochran-Mantel-Haenszel test adjusted for randomization strata. These results show a 10-fold improvement in ORR in the ramucirumab arm when compared to the placebo arm. The disease control rates (complete response+partial response+stable disease) in the ramucirumab arm and placebo arm were 56.2% (95% CI=50.4, 61.8) and 45.7% (95% CI=40.0, 51.6), respectively, with a p-value of 0.0110 using the same test for overall response rate.

[0114] The secondary endpoints PFS, TTP and ORR demonstrate the benefit of ramucirumab DP as second-line treatment in patients with HCC following first-line therapy with sorafenib.

Association of Baseline Alpha-Fetoprotein (AFP) and Observed Treatment Effect for Ramucirumab:

[0115] A poorer prognosis for HCC patients is associated with elevated AFP, macro-vascular invasion, and higher stage of disease (i.e., extrahepatic metastases), increased micro-vessel density and increased VEGF expression. The elevated AFP population in this trial shares several of these factors.

[0116] When evaluating OS in the placebo arm, patients with AFP levels greater than 400 ng/mL have a worse prognosis than patients with AFP levels less than or equal to 400ng/mL. This indicates that AFP is a prognostic factor for OS in HCC patients.

[0117] A pre-specified subgroup analysis was performed in the ITT population with baseline AFP<400 (310 patients) or >400 ng/mL (250 patients). In patients with a baseline AFP>400 ng/mL, the median OS in the ramucirumab arm was 7.8 months, and the median OS in the placebo arm was 4.2 months. An unexpected improvement of 3.6 months was observed. The stratified HR was 0.674 (95% CI: 0.508, 0.895; p=0.0059), indicating a reduction in the risk of death by 32.6%. No improvement in median OS was observed in patients with a baseline AFP<400 ng/mL. In patients with a baseline AFP<400 ng/mL, the median OS in the ramucirumab arm was 10.1 months, and the median OS in the placebo arm was 11.8 months. The stratified HR was 1.093 (95% CI: 0.836, 1.428; p =0.5059). Baseline AFP and ramucirumab treatment demonstrated a significant subgroup-by-treatment interaction on OS HR with a p=0.0272.

[0118] A pre-specified subgroup analysis of PFS in the Ramucirumab DP arm was performed in the patient populations defined by an alpha-fetoprotein (AFP) serum level or <400 ng/mL. In the population with a baseline AFP 400 ng/mL, the PFS HR was 0.691 (95% CI: 0.530, 0.901) (p=0.0106), and in the population with a baseline AFP <400 ng/mL, the PFS HR was 0.645 (95% CI: 0.506, 0.821) (p<0.0001). The comparable PFS results observed in patient populations with a baseline AFP≧and <400 ng/mL suggest ramucirumab has antitumor activity irrespective of baseline AFP.

[0119] The benefit of ramucirumab was further assessed in the Study patient populations defined by a baseline AFP<or ≧1.5×Upper Limit of Normal (ULN). ULN AFP levels for these analyses is determined separately by each laboratory, though an AFP of 10 ng/mL is a typical value for the ULN used by local laboratories in this Study. Analysis of HR and median survival times was performed to assess the relationship between baseline AFP and the observed OS results.

[0120] In patients with AFP levels >1.5×ULN, the median OS in the ramucirumab arm was 8.6 months (95% CI: 7.2, 10.1), and the median OS in the placebo arm was 5.7 months (95% CI: 4.7, 7.0) with a stratified HR of 0.749 (CI: 0.603, 0.930) and stratified Log-rank p-value of p=0.0088. A median OS improvement of 2.9 months was observed; a survival improvement that is similar in magnitude to that observed in patients with AFP levels >400 ng/mL. Subgroup-by-treatment interaction testing for a baseline AFP<or ≧1.5×ULN with the OS treatment effect demonstrated a p-value of 0.0372. The results indicate that the survival benefit observed in the pre-specified analyses may be extended to patients with modestly elevated baseline AFP.

[0121] In patients with an AFP<1.5×ULN, the median OS in the ramucirumab arm was 11.6 months compared to 16.4 months for the placebo arm. The stratified HR was 1.337 (95% CI: (0.874, 2.046)), with a p-value of 0.1789. Thus, the population defined by a baseline AFP<1.5×ULN identifies the subgroup unlikely to derive an OS benefit from ramucirumab treatment.

[0122] More surprisingly, for patient populations with a baseline AFP>10 ng/mL or any higher threshold, the difference in median OS between the ramucirumab and placebo treatment arms is maintained at approximately 3 months, despite the fact that the absolute survival times become progressively shorter in populations defined by increasing thresholds of AFP. In addition, patient populations with a baseline AFP≧10 ng/mL or any higher threshold, the p-value associated with the HR is p<0.05 over a range of AFP values where the confidence in the results is not limited by sample size. For patient populations with a baseline AFP≧10 ng/mL or any higher threshold the HRs are in the range of approximately 0.50 to 0.75, becoming generally more favorable with increasing thresholds of AFP.

[0123] A robust and clinically meaningful improvement in OS, comparing the ramucirumab arm with the placebo arm, was observed using both AFP threshold values, AFP≧400 ng/mL and AFP≧1.5×ULN. This survival improvement was consistently 3 months, even in the patient population with poor prognosis HCC and highly elevated (≧400 ng/mL) levels of baseline AFP. These results demonstrate the consistent predictive value of an elevated baseline AFP for ramucirumab treatment.