Phase II Trial of Bortezomib Plus Doxorubicin in Hepatocellular

Carcinoma (E6202): A Trial of the Eastern Cooperative Oncology Group:

Berlin J1, Powell M2, Su Y1, Horton L1, Short S1, Richmond A1, Kauh JSW3,

Staley C3, Mulcahy M4, Benson III AB4. 1Vanderbilt University/Vanderbilt-Ingram Cancer Center,

2Dana Farber Cancer Institute, 3Emory University, 4Northwestern University

Abstract

Background: Until ASCO 2007, the there was no proven systemic therapy for HCC, but dox was used often because of a response rate (RR) of up to 10%. We tested the effects of bor, dox and bor + dox in HCC cell lines and mouse models and found dox + bor to be at least additive compared to dox alone. Methods: Eligible pts had biopsy proven HCC with no prior chemotherapy or hormonal therapy, ECOG PS 0-2, with measurable and biopsiable disease. Pts had adequate bone marrow function (lower levels allowed for splenomegaly), bilirubin ≤ 2.0 mg/dl, Child’sPugh class A or B cirrhosis, INR ≤ 1.5, no peripheral neuropathy of grade 2 or higher and normal ejection fraction. Primary endpoint is RR. Null hypothesis = 10% RR. 40 pts were planned (37 eligible) to give 91% power to detect RR of 27% (7 responses) with 1-sided significance of 0.07. Secondary endpoints were toxicity, survival (OS) and progression-free survival (PFS). Dox (20 mg/m2) was given days 1, 8 (day 1 dox was omitted in cycle 1) and Bor was given days 1, 4, 8 and 11 of a 21-day cycle. Serum was analyzed prior to treatment, cycle 1 day 8 and cycle 2 day 8 for changes in chemokines/cytokines (CKS). Results: 42 pts accrued, 39 confirmed eligible: 28 male, 11 female; 27 white, 9 African American, 3 other; PS = 0, 6, PS = 1, 28, PS =2, 5. 1 response (2.3%) was seen. Median OS was 5.7 months (4.4, 7.9) and PFS was 2.4 months (2.1, 3.0). 28/39 had grade 3 toxicity, 11 had grade 4. Most common toxicities were grad 3 leukocytes (11 pts), grade 3 platelets (8 pts) and grade 4 platelets (8 pts). including: CKS showed changes in serum levels of GROα, MIP-1α, IL-6 and IL-8 in several pts. Conclusions: dox + bor did not show significant activity in HCC. The regimen was generally well-tolerated with mostly hematologic toxicity and no toxic deaths. Bor caused changes in several CKS levels in pts with HCC. We will analyze the lab data to try to correlate with clinical effects (efficacy and toxicity) prior to the ASCO 2008 meeting.

Supported by: R21 CA 099269, Eastern Cooperative Oncology Group (Robert L. Comis), and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA17145 and from the National Cancer Institute, National

Institutes of Health and the Department of Health and Human Services

Background

• In 2002, when this study was designed, doxorubicin was the de facto standard of care in HCC with a 0-10% Response Rate

• A single agent bortezomib trial reported at ASCO had 7/20 patients with stable disease

• At Vanderbilt-Ingram Cancer Center, pre-clinical studies showed in HCC models– Activity of bortezomib > activity of doxorubicin– Additive activity for bortezomib + doxorubicin

Methods• Phase II trial, single-stage design

– Early stopping rule designed for excessive toxicity

• Primary Endpoint– 27% Response Rate considered positive– 10% Response Rate is null hypothesis– 40 patients needed for 37 eligible

• 91% power to detect alternative hypothesis with 1-sided significance level of 0.07

• Secondary Endpoints– 4.5 month PFS (21% increase from 50% to 71%)

• 84% power to detect alternative hypothesis with 1-sided significance of 0.07

– Overall Survival– Time to Tumor Progression

Key Eligibility

• Unresectable HCC• Measurable Disease by RECIST, potentially amenable to

biopsy• ECOG PS 0-2• Adequate organ function

– Creatinine < 2.0 mg/dl– Child Pugh A or B only– Platelet ≥ 100K or ≥ 75 K if splenomegaly is present– ANC ≥ 1.5 or ≥ 1.0 if splenomegaly is present– Bili ≤ 2.0 mg/dl– AST and Alk phos ≤ 5x ULN

• Prior Liver Transplant allowed

Key Ineligibility

• No prior systemic hormonal therapy, chemotherapy or hepatic chemotherapy although bland embolization, ethanol injection, RFA were allowed

• EF < 50%

• Peripheral neuropathy > grade 1

• INR > 1.5

Treatment Plan

• Bortezomib (supplied by CTEP/NCI) 1.3 mg/m2 days 1, 4, 8 and 11 of a 21-day cycle

• Doxorubicin 20mg/m2 days 1 and 8, except on cycle 1 when it is administered day 8 only (and if bili 1.3-2, then dose is 15 mg/m2 on days 1 and 8)—21-day cycle

• Maximum cycles = 10• Disease evaluation q 3 cycles and at end of

treatment (Response assessed by RECIST)• Routine ECHO/MUGA scans

Correlates

• Optional tumor biopsies on day 1 and day 8 were requested initially, but after biopsies had too little tissue on most early samples, this was discontinued

• Blood was drawn cycles 1, 2 and 9, 10 on days 1 and 8 for– Serum: IL-1, IL-8, VEGF and MIP-1α

– WBC’s: p21, p27, p53, BCL-2 and Bax

ResultsParameter N (total = 39*) %

Sex: Male

Female

28

11

71.8

28.2

Median Age: 58

Ethnicity: White

African

American

Other

27

9

3

69.3

23.1

7.7

ECOG PS: 0

1

2

6

28

5

15.4

71.8

12.8

*42 patients enrolled, 39 eligible

Treatment

• Prior Treatment:– 4 patients had prior liver transplants– 2 patients had prior bland emoblizations

• On Study– Median of 3 cycles administered

• Range: 1-11• 13 patients (33%) did not complete the first 3 cycles, 5 of whom had

only 1 cycle

• Off-study– 22 patients (56.4%) stopped due to progression– 10 patients (26.4%) stopped due to AE’s, side effects or

complications– 3 patients (7.7%) died on study– 4 patients (10.3%) withdrew consent or refused further treatment

without progressive disease

Toxicities I

Toxicity Grade 1,2 Grade 3 Grade 4

Hemoglobin 31 1 1

Platelets 12 8 8

Leukocytes 13 11

Neutrophils 11 6 2

Alkaline Phos 15 1

AST (SGOT) 22 2

Bilirubin 10

Creatinine 9

INR 2

Toxicities IIToxicity Grade 1,2 Grade 3 Grade 4

Fatigue 15 7

Anorexia 14

Diarrhea 9 5

Nausea 13 1

Vomiting 5 1

Constipation 9

Taste Disturbance 7

Dehydration 1 2

Sensory Neuropathy 10

Response

Response N=39 %

PR 1 2.6

Stable 10 25.6

Progression 17 43.6

Unevaluable 11 28.2

Reasons for Unevaluable Pts:

4 patients died, not related to therapy

5 patients without available follow-up scans

2 patients switched type of scan performed (MRI vs CT)

Treatm ent Arm ALIVEDEAD MEDIANTOTAL

A 39 30 9 5.7

Pro

bab

ility

Figure 1. O vera ll S urviva l - E 6202

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O vera ll Surv iva l (M onths)

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Med Survival 5.7 months (90% CI = 4.4, 7.9 months)

Treatment Arm MEDIANTOTALA 39 33 6 2.4

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Figure 2. PFS - E6202

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Figure 2. PFS - E6202

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Figure 2. PFS - E6202

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PFS EVENT CENSORED

Median PFS = 2.4 months (90% CI 2.1-3.0 months)

Change of RelAp65 EMSA Value for Cycle 1

-120

-100

-80

-60

-40

-20

0

20

40

Individual Patient Increase or Decrease in Nuclear RelA DetectedIn EMSA . Each diamond represents one patient’s change during cycle 1.

Change of RelAp65 EMSA Value for Cycle 2

-100

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100

150

200

Individual Patient Increase or Decrease in Nuclear RelA DetectedIn EMSA . Each diamond represents one patient’s change during cycle 2

Change in Chemokine Levels Between Treatment Cycles

Conclusions

• The combination of of doxorubicin and bortezomib was tolerable in a relatively healthy HCC population

• The combination of doxorubicin and bortezomib is not sufficiently promising to investigate it further in HCC

• Laboratory correlatives suggest that some patients experienced changes suggestive of bortezomib affecting its target– Clinical correlation with changes in laboratory

parameters is pending