A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma- A North Central Cancer Treatment Group Study, N057E

Abstract

Background

There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). ABI-007 is an albumin bound formulation of paclitaxel which has demonstrated single agent activity against metastatic melanoma.

Methods

A parallel phase II trial was conducted in patients with unresectable stage IV melanoma who were either chemotherapy naïve (CN) or were previously treated (PT). The treatment regimen consisted of ABI-007 (100 mg/m²) and carboplatin area under the curve (AUC2) administered on days 1, 8, and 15, every 28 days. The primary aim of this study was objective response rate (RECIST).

Results

76 patients (41 CN and 35 PT) enrolled from 11/2006 – 7/2007. Three patients withdrew consent prior to starting treatment. The median number of treatment cycles was 4. There were 10 (25.6%) responses (1 complete response [CR ] and 9 partial responses [PRs]) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) responses ( 3 PRs) in the PT cohort (90% CI: 2.5–21.3%). Median PFS was 4.5 months (CN) and 4.1 months (PT). Median overall survival (OS) was 11.1 months (CN) and 10.9 (PT). Severe toxicities in both groups [Common Terminology Criteria for Adverse Effects (CTCAE) ≥ grade 3] included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting.

Conclusions

The weekly combination of ABI-007 and carboplatin appears to be moderately well tolerated with promising clinical activity as therapy in patients who are CN and modest anti-tumor activity in those who had PT

INTRODUCTION

Patients diagnosed with metastatic (stage IV) melanoma face a poor prognosis, with a median overall survival (OS) time of 6–9 months and 5 year survival of approximately 5%¹. Currently, dacarbazine remains the only FDA approved chemotherapy agent for stage IV melanoma with response rates of less than 20% and no improvement in OS². Several combination regimens have produced response rates of 30–50% but with higher toxicity rates and no impact on OS^3–6. Thus, the need for more effective therapy for metastatic melanoma remains.

The combination of carboplatin and paclitaxel has been shown to be active in a wide range of malignancies including metastatic melanoma^7–12. Response rates in a phase II trial setting and a retrospective review showed an objective response rate (ORR) of this combination were approximately 20–25%^7,8, with a third small randomized phase II trial showing no objective responses but stabilization of disease of approximately 20% in the combination paclitaxel + carboplatin arm⁹. In addition a recently reported randomized phase II trial utilizing paclitaxel, carboplatin +/− bevacizumab/placebo showed the response rate (RR) for the control arm to be approximately 16.4% ¹⁰. Two Phase III trials examining the impact of adding sorafenib to paclitaxel and carboplatin (in both chemotherapy-naïve¹¹ as well as previously treated¹² settings) reported an ORR of 16% and 11% respectively in each of the paclitaxel/carboplatin arms with a progression free survival (PFS) of 4.1 mons¹¹ and 17.9 weeks¹². Treatments were generally well-tolerated with cytopenias, neuropathy, nausea, vomiting and hypersensitivity reactions as the primary toxicities.

Given the modest clinical efficacy of the combination of paclitaxel and carboplatin for therapy of stage IV melanoma ^7-12 and the development of ABI-007 (Abraxane^™, nab-paclitaxel), a solvent free, albumin bound formulation of paclitaxel designed to reduce the Cremophor vehicle associated toxicity of paclitaxel suggested examining the anti-tumor of combination of ABI-007 and carboplatin.

There are at least two potential advantages for the use of ABI-007 in place of paclitaxel in combination with carboplatin for patients with metastatic melanoma. First is the ability of ABI-007 to deliver a higher dose of paclitaxel. This was clearly demonstrated in the metastatic breast cancer setting in a randomized phase III study comparing ABI-007 at 260 mg/m² to paclitaxel 175 mg/m² on an every 3 weeks schedule¹³. The ABI-007 arm demonstrated significantly higher response rates and time to progression, as well as a significantly lower incidence of grade 3 or 4 neutropenia, despite the increased dose of paclitaxel being administered in the ABI-007 arm¹³. There was increased incidence of grade ≥3 peripheral neuropathy in the ABI-007 arm, but with a more rapid recovery. Additionally, ABI-007 obviates “allergic” pre-medications and shortens infusion time relative to paclitaxel. Of particular interest for melanoma is the ability of ABI-007 (and not paclitaxel) to bind SPARC (secreted protein acidic and rich in cysteine), a protein highly expressed on malignant melanocytes¹⁴. This is a potentially important pathway in delivering ABI-007 to the tumor at high concentrations ^{14, 15}. This may have explained the results of single agent ABI-007 therapy in patients with previously treated stage IV melanoma demonstrating clinical activity superior to prior studies of Taxol¹⁶ and as such, the substitution of ABI-007 for paclitaxel in combination with carboplatin for the treatment of metastatic melanoma may offer greater clinical benefit.

In a phase I trial of 3 different schedules of ABI-007 administered in combination with carboplatin in patients with solid tumors found a maximum tolerated dose for ABI-007 (MTD) at 300mg/m² (every 3 weeks); 100 mg/m² (d. 1, 8, and 15 q 28 d) and 125 mg/m² (d 1 and 8 q 21 d) all with carboplatin AUC 6 day 1^{17, 18}. This trial enrolled 10 (of 41) patients with metastatic melanoma, of whom 3 patients had a PR on the weekly regimen and 3 patients had stable disease (SD) on the every 3 week regimen^{17, 18}. There was a higher degree of severe (≥grade 3) neutropenia and thrombocytopenia with the weekly regimen.

Herein we present the results of a phase II clinical trial utilizing a combination of carboplatin (AUC 2) and ABI-007 (100mg/m2) administered on a weekly regimen (days 1, 8 and 15 of a 28 day treatment cycle) administered to both chemotherapy naïve and previously treated (no prior exposure to taxanes) patients with stage IV melanoma. We selected the weekly dosing regimen of carboplatin in the hope of decreasing the incidence of ≥grade 3 cytopenias as was seen in the phase I trial.

PATIENTS AND METHODS

This study consisted of two parallel phase II clinical trials (cohorts) to assess the anti-tumor activity and safety profile of the combination of carboplatin and ABI-007 in patients with unresectable stage IV malignant melanoma that were either previously treated with chemotherapy in the metastatic setting (cohort 1) or were chemotherapy naïve in the metastatic setting (cohort 2). This study was a multi-institution cooperative group study conducted through the North Central Cancer Treatment Group (NCCTG). All patients provided signed informed written consent. This study was approved by the institutional review boards of all participating institutions.

Eligible patients must have been ≥ 18 years of age with unresectable, histologically confirmed stage IV melanoma. Additional eligibility criteria included measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, life expectancy ≥ 3 months, adequate hematologic and hepatic function, ≥ 4weeks since their last chemotherapy (cohort 1 only), radiation therapy, or immunotherapy. Exclusion criteria included: any prior treatment with platinum or taxanes (cohorts 1 & 2), any prior chemotherapy for metastatic disease (cohort 2), active infection, New York Heart Association Class III or IV, peripheral neuropathy ≥ grade 2; other malignancy <5 years (except for non-melanomatous skin cancer or carcinoma in situ of the cervix) or untreated metastatic melanoma to the brain or progression of brain metastasis within 3 months of study entry. Women who were pregnant or breast feeding were not enrolled.

Study Design and Treatment

Eligible patients (both cohorts) were treated with 100 mg/m² of ABI-007 by intravenous infusion over 30 minutes followed by carboplatin with a target AUC of 2 (by Calvert formula with Cockroft and Gault Equation and actual body weight) over 30 minutes on days 1, 8, and 15 of a 28 day cycle, for a maximum of 8 cycles. If patients did not develop excessive toxicity or progressive disease, treatment beyond 8 cycles was at the discretion of the treating physician.

Within 14 days of registration, patients underwent a complete physical exam, assessment of performance status, complete blood cell count (CBC), comprehensive metabolic panel including lactic dehydrogenase (LDH), and a tumor assessment by conventional CT or MRI or spiral CT. Prior to each cycle of treatment, patients underwent a physical exam, toxicity assessments, and blood draws for hematologic and chemistry groups. Tumor status was assessed every 8 weeks until progression using RECIST criteria.

On day 1 of each treatment cycle, treatment was held if: absolute neutrophil count (ANC) < 1,500/mm³ or platelet count (PLT) < 100,000/mm³ or patient developed a grade ≥2 Aspartate Aminotransferase (AST), grade ≥2 neuropathy or other grade ≥3 non-hematologic toxicity. When patients had recovered from these toxicities, treatment was re-started with a 20% dose reduction in both agents. On days 8 or 15 of each treatment cycle, treatment was omitted if: ANC < 1,000/mm³ or PLT < 100,000/mm³ or patient developed either a grade ≥2 neuropathy or grade ≥3 non-hematologic toxicity. Study treatment was terminated if toxicities did not recover to acceptable levels within 4 weeks and/or if patients required a third dose reduction due to toxicity.

All patients received standard supportive care, including antiemetics, antibiotics, blood/platelet transfusions, erythropoietin and colony stimulating factors at the discretion of the treating physician.

Statistical Considerations

The primary endpoint for both trials was the clinical response rate defined as the number of eligible patients whose disease met the RECIST criteria 1.0 for response, that is, a complete (CR) or partial response (PR) on two consecutive evaluations at least 8 weeks apart divided by the number of eligible patients who began treatment. For those patients whose disease responded to treatment, the duration of response was defined as the time from the first tumor evaluation where an objective status of CR or PR was assigned, to date of disease progression.

For cohort 1 (prior chemotherapy, PT), a sample of 35 patients was to be enrolled so that a one-sided alpha=0.10 one sample test of proportions would have at least a 90% chance of detecting whether the ORR was greater than 5% when it was at least 20%. If at least 4 patients of the 35 eligible patients enrolled had a tumor response without excessive toxicity, the regimen would be considered for further testing in this patient population. For cohort 2 (chemotherapy naïve, CN) a sample of 35 patients was to be enrolled so that a one-sided alpha=0.10 one sample test of proportions would have at least a 90% chance of detecting whether the ORR was greater than 15% when it was at least 35%. If at least 9 patients of the 35 eligible patients enrolled had a tumor response without excessive toxicity, the regimen would be considered for further testing in this patient population.

A 90% confidence interval for the response rate was constructed using the properties of the binomial distribution. Progression-free survival time was defined as the time elapsed from registration to progression of disease or death without prior documentation of progressive disease. Survival time was defined as the time elapsed from registration to death due to any cause. Time to event distributions was estimated using the Kaplan-Meier method¹⁹. Toxicities were graded and attribution assigned by treating physicians using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

RESULTS

Patient Characteristics

Seventy six patients were accrued onto this trial between November 15, 2006 and July 31, 2007. Three patients (1 PT and 2 CN) withdrew consent prior to the start of treatment. After the close of enrollment, one patient who was registered as having had prior chemotherapy was found to have received immunotherapy not chemotherapy and as such was reassigned to the CN cohort. Thus, the PT cohort includes the 34 patients (67.6% male) aged 28 to 84 years (median age: 60 years) who began study treatment and the CN cohort includes the 39 patients (59.0% male) aged 23 to 81 years (median age: 59 years) who began study treatment. The characteristics of these cohorts are presented in Table 1.

Table 1.

Patient Characteristics

Patient Characteristics	Previously treated Patients (Cohort 1) n=34	Chemotherapy Naïve Patients (Cohort 2) n=39
Median age (range)	60 years (28–84)	59 years (23–91)
Male	23 (67.6%)	23 (59.0%)
M stage
M1a	5 (14.7%)	7 (18.0%)
M1b	11 (32.4%)	13 (33.3%)
M1c	18 (52.9%)	19 (48.7%)
ECOG performance status
0	22 (64.7%)	24 (61.5%)
1	11 (32.4%)	13 (33.3%)
2	1 (2.9%)	2 (5.1%)
Pre-existing signs and symptoms
grade 3 fatigue	1 (2.9%)	--------
grade 2 fatigue	3 (8.8%)	4 (10.3%)
grade 1 neuro-sensory difficulties	5 (14.7%)	5 (12.8%)
Prior therapies
radiation therapy	16 (47.1%)	8 (20.5%)
immunologic therapy	8 (23.5%)	10 (25.6%)
hormonal therapy	--------	2 (5.1%)
vaccine therapy	3 (8.8%)	2 (5.1%)
chemotherapy *	34 (100%)	0
Temozolomide	23 (67.6%)
Temozolomide + thalidomide	2(5.8%)
Everolimus	4(11.8%)
Dacarbazine	7 (20.5%)
Elevated LDH at time of registration
Yes	8 (24%)	16 (41%)
No	19 (56%)	18 (46%)
Baseline LDH not provided	7 (20%)	5 (13%)

^*Two patients had received 2 prior chemotherapy regimens

Treatment Course

Cohort 1 (PT)

At the time of this report, all patients have discontinued study treatment. The median number of cycles administered was 4 cycles (total: 135 cycles, range: 1–10). Fifteen patients (44.1%) received 85% or more of the total ABI-007 dose they should have received for their time on treatment. Twenty one patients (61.8%) either omitted day 8 and/or 15 of treatment (8 pts); had at least one dose reduction (3 pts), or both (10 pts.), primarily due to severe neutropenia, fatigue, and neuropathy. The most common severe (≥ grade 3) toxicities [possibly, probably, or definitely related to treatment] reported included: neutropenia (41%), leukopenia (15%), lymphopenia (3%), vomiting (3%), nausea (3%), and peripheral nerve infection: herpes zoster (3%). Grade 2 neuro-motor and neuro-sensory difficulties were reported in 3% and 9% of patients respectively (Table 2). The reasons for treatment discontinuation included: progression of disease (27 patients), excessive toxicity (need for a third dose reduction [3 pts], persistent fatigue [1 pt], and severe allergic reaction [1 pt]), and refusal to continue treatment (2 pts).

Table 2.

Toxicities reported to be possibly, probably, or definitely related to treatment by at least 10% of those who began treatment

	Previously treated Patients (Cohort 1) n=34		Chemotherapy Naïve Patients (Cohort 2) n=39
Toxicity	Any grade	Grade 3 or 4	Any grade	Grade 3 or 4
Hematologic
neutropenia	59%	41%	59%	28%
thrombocytopenia	41%	0%	44%	5%
leukopenia	26%	15%	21%	3%
lymphopenia	6%	3%	8%	0%
anemia	68%	0%	72%	0%
Non-hematologic
fatigue	56%	3%	72%	3%
nausea	56%	3%	46%	3%
neuro-sensory	47%	0%	33%	5%
vomiting	26%	3%	15%	3%
arthralgia	9%	0%	10%	0%
myalgia	18%	0%	8%	0%
peripheral nerve infection	3%	3%	---	---

Cohort 2 (CN)

At the time of this report, all but 1 of 39 patients has discontinued study treatment. The median number of cycles administered was 4 cycles (total: 194 cycles, range: 1–26). Twenty-four patients (65.1%) received 85% or more of the total ABI-007 dose they should have received for their time on treatment. Twenty five patients (64.1%) either omitted day 8 and/or 15 of treatment (12 pts); had at least one dose reduction (4 pts), or both (9 pts.), primarily due to severe neutropenia and neuropathy. The primary reason for study discontinuation was progression of disease (28 patients). There was one treatment related death in this cohort. This was a 79-year-old male with M1b stage disease who died 26 days after enrolling having completed one cycle of treatment. He developed grade 4 febrile neutropenia, diarrhea, infectious colitis and hypotension. The most common severe (≥grade 3) toxicities [possibly, probably, or definitely related to treatment] reported included: neutropenia (28%), thrombocytopenia (5%), neurosensory (5%), vomiting (3%), nausea (3%), fatigue (3%), and leukopenia (3%). Grade 2 neuro-sensory difficulties were reported in 3% of patients. (Table 2) The reasons for treatment discontinuation included: progression of disease (28 patients), excessive toxicity (need for a third dose reduction [1 pt], neuropathies [2 pts], and severe allergic reaction [1 pt], severe nausea and vomiting [1 pt]), death (1 pt), and refusal to continue treatment (1 pt), desire for alternative treatment (1 pt), and completion of 8 cycles of treatment (3 pts).

Clinical Efficacy

Cohort 1 (PT)

All but one patient (who refused further follow-up) were followed for a minimum of 9.0 months or until death. Three patients had a partial tumor response lasting 3.2, 3.5, and 11.6 months, respectively. No CRs were reported. Thus, the tumor response rate was 8.8% (90%CI: 2.5–21.3%). At last contact, 1 patient was alive without disease progression, 6 patients are alive with disease progression, and 27 patients have died of their disease. The median PFS was 4.2 months and the median OS was 10.9 months (Figure 1).

Figure 1.

Distribution of progression-free and overall survival times among the patients who did not have prior chemotherapy in the metastatic setting.

Cohort 2 (CN)

All patients were followed for a minimum of 1.7 years or until death. Among the first 35 patients enrolled, there were 9 (25.7%; 90%CI: 14.1–40.6%) patients who had a tumor response (1-CR and 8-PRs). Among all 39 patients enrolled, there were 10 (25.6%; 90%CI: 14.6–39.6%) patients who had a tumor response (1-CR and 9-PRs) lasting 4.0 to 30.6⁺ months (median: 12.1 months). Thus, the tumor response rate was 25.6% (90%CI: 14.6–39.6%). At last contact, 3 patients are alive without disease progression, 4 patients are alive with disease progression, and 32 patients have died of disease. The median PFS was 4.3 months and the median OS was 11.1 months (Figure 2).

Figure 2.

Distribution of progression-free and overall survival times among the patients who did have prior chemotherapy in the metastatic setting.

DISCUSSION

The results of the presented study in patients with metastatic melanoma demonstrate that the combination of ABI-007 and carboplatin has promising clinical activity for patients who are chemotherapy naïve but fails to meet to meet/exceed the study threshold for promising clinical activity in patients who have been previously treated in the metastatic setting. Overall, treatment was moderately well tolerated with the main toxicities being nausea, vomiting, peripheral neuropathy, and cytopenias (neutropenia, thrombocytopenia, leukopenia).

Previous studies have shown that a taxane based regimen in combination with carboplatin has some activity in melanoma^7–12 Hodi et al⁷ reported the results of a small phase II pilot study utilizing an every 3 week regimen of paclitaxel 175 mg/m² and carboplatin AUC 7.5 on day 1. Of the 15 patients enrolled, 3 had PR’s and 7 had stable disease with a median survival of 9 months. Zimpfer-Rechner et al. conducted a randomized phase II study utilizing single agent paclitaxel (100 mg/m²-d 1) versus the paclitaxel (80 mg/m²-d.1) and carboplatin (200 mg/m² d. 1). The dosing on this regimen was quite different with paclitaxel +/− carboplatin being utilized weekly for 6 weeks on and 2 weeks off. Forty patients were enrolled with 32 being evaluable. There were no responses reported in the combination arm but the SD rate was 20%⁹. Rao et al⁸ in a single institution retrospective review of 31 patients treated with the combination as second line therapy primarily administered as a weekly regimen (paclitaxel 100 mg/m² and carboplatin AUC 2 d. 1, 8, and 15, every 28 days) reported a 26% PR rate and a 19% SD rate⁸. Finally two randomized phase III trials examining the impact of adding sorafenib to paclitaxel and carboplatin found a 11%¹² and a 16%¹¹ ORR in the paclitaxel/carboplatin arms. Replacing paclitaxel with ABI-007 in the hopes of improving the toxicity profile and thus increasing the amount of drug given resulted in promising anti-tumor activity (ORR of 25.6%) among CN patients but not the PT patients. The toxicity profile of this study showed less toxicity than that of the two PRISM studies ^{11, 12}, with less overall grade 3 or 4 cytopenias, fatigue, and sensory neuropathy. The etiology of this is not completely clear, but most likely is a result of replacing paclitaxel with ABI-007 and a lower weekly carboplatin dosing. However allergic reactions were significantly reduced with the use of ABI-007. The present study also shows slightly better survival rates to that of Ipilumimab (PFS 2.9 mons and OS 10.1 mons) ²⁰. In summary, the presented data confirm that ABI-007 approximates efficacy and toxicity of paclitaxel when combined with carboplatin for the treatment of patients with metastatic melanoma. While such regimens have not been formally compared in a randomized controlled study, the combination of ABI-007 and carboplatin is a viable option when CN patients cannot tolerate conventional paclitaxel therapy. Additionally, recent evidence, although not definitive, of the combination of bevacizumab with paclitaxel and carboplatin seem to suggest a better clinical outcome as compared to prior Food and Drug Administration (FDA) approved therapies^{10, 21}. Whether or not the addition of bevacizumab to the combination of ABI-007 and carboplatin will yield similar (or superior) results to those of Taxol/carboplatin, is the subject of an ongoing study.