Morton, Roscoe F.

PURPOSE Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.

Background Previous studies have established that higher baseline quality of life (QOL) scores are associated with improved survival in patients with metastatic colorectal cancer (mCRC). We examined the relationship between overall survival (OS) and baseline QOL. Patients and Methods A total of 1 247 patients with mCRC participating in N9741 (comparing bolus 5-FU/LV, irinotecan [IFL] vs infusional 5-FU/leucovorin [LV]/oxaliplatin [FOLFOX] vs. irinotecan/oxaliplatin [IROX]) provided data at baseline on overall QOL using a single-item linear analogue self-assessment (LASA) 0–100 point scale. The association of OS according to clinically deficient (defined as CD-QOL, score 0–50) vs not clinically deficient (nCD-QOL, score 51–100) baseline QOL scores was tested. A multivariable analysis using Cox proportional hazards modeling was performed to adjust for the effects of multiple baseline factors. An exploratory analysis was performed evaluating OS according to baseline QOL status among patients who did or did not receive second-line therapy. Results Baseline QOL was a strong predictor of OS for the whole cohort (CD-QOL vs nCD-QOL: 11.2 months vs 18.4 months, P < .0001), and in each arm IFL 12.4 vs 15.1 months, FOLFOX 11.1 months vs 20.6 months, and IROX 8.9 months vs 18.1 months. Baseline QOL was associated with baseline performance status (PS) ( P < .0001). After adjusting for PS and treatment arm, baseline QOL was still associated with OS ( P = .017). Conclusions Baseline QOL is an independent prognostic factor for OS in patients with mCRC. The demonstration that patient-assessed QOL and PS are independent prognostic indicators suggests that these assessments provide important complementary prognostic information.

PURPOSE The androgen receptor (AR) is expressed (+) in a subset of salivary gland cancers (SGCs). This phase II trial evaluated the efficacy of the antiandrogen enzalutamide in AR+ SGC. METHODS Patients with locally advanced/unresectable or metastatic AR+ SGCs were enrolled. Enzalutamide (160 mg) was given orally once daily. The primary end point was the best overall response rate per RECIST v1.1 within eight cycles. Confirmed responses in ≥ 5 of 41 patients would be considered promising. Secondary end points were progression-free survival, overall survival, and safety. RESULTS Forty-six patients were enrolled; 30 (65.2%) received prior systemic therapy, including 13 (28.3%) with AR-targeted drugs. Of seven (15.2%) partial responses (PRs), only two (4.3%) were confirmed per protocol and counted toward the primary end point. Twenty-four patients (52.2%) had stable disease; 15 (32.6%) had progression of disease as best response. Twenty-six patients (56.5%) experienced tumor regression in target lesions; 18 (39.1%) had partial response/stable disease ≥ 6 months. Tumor regressions were observed in female patients (5 of 6 [83.3%]) and those who received prior AR– (6 of 13 [46.2%]) or human epidermal growth factor receptor 2–targeted therapies (5 of 8 [62.5%]). Three patients remained on treatment at data cutoff (duration, 32.2-49.8 months). The median progression-free survival was 5.6 months (95% CI, 3.7 to 7.5); the median overall survival was 17.0 months (95% CI, 11.8 to 30.0). The most common adverse events were fatigue, hypertension, hot flashes, and weight loss. Total and free testosterone levels increased by a mean of 61.2% and 48.8%, respectively, after enzalutamide. CONCLUSION Enzalutamide demonstrated limited activity in AR+ SGC, failing to meet protocol-defined success in part because of a lack of response durability. Strategies to enhance the efficacy of antiandrogen therapy are needed.

9055 Background: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). Nab-P is an albumin-bound paclitaxel with ability to bind SPARC (secreted protein acid rich in cysteine), that is overexpressed in MM and associated with poor prognosis. This study explores the clinical activity of the combination of nab-P and C in patients (pts) with stage IV melanoma and SPARC correlatives. Methods: A parallel phase II trial was conducted in pts with unresectable stage IV melanoma, who were either chemotherapy naïve (CN) or were previously treated (PT). A treatment regimen consisting of nab-P (100 mg/m2) and C (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs ≥35% in the CN group and ≤5% vs ≥ 20% in the PT cohort. Major eligibility criteria: ≥18 years of age, ECOG PS ≤2, adequate organ function, platinum or taxane naive, peripheral neuropathy < grade 2, and no untreated brain metastasis; no pregnant and/or nursing women. Tumor tissue was tested for SPARC and level 3 immunohistochemical staining was considered positive. Results: 76 pts (41-CN and 35 PT) enrolled from 11/2006 - 7/2007, 3 pts (2-CN, 1-PT) cancelled prior to starting treatment. The median number of cycles administered was 4 (range 1–18-CN and 1–10-PT). There were 11 (28.2%) confirmed responses (1 CR and 10 PRs) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) confirmed 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 OS was 11.1 months (CN) and 10.9 months (PT).The most common severe toxicities in both groups (CTCAE ≥ grade 3) included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting. PFS was not affected by SPARC positivity; however, based on limited data there is some evidence that OS may be longer with tumoral SPARC positivity (10.0 vs 12.8 mo; SPARC negative vs SPARC positive). Conclusions: The weekly combination of nab-P and C appears to be well tolerated with promising clinical activity as front line or salvage therapy in pts with MM. SPARC positivity may be associated with improved OS. No significant financial relationships to disclose.

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

7532 Background: Mantle Cell Lymphoma (MCL) is characterized by t(11;14) resulting in over expression of cyclin D1, a member of the phosphatidylinosital 3-kinase (PI3K) pathway. Temsirolimus is a novel inhibitor of the mammalian target of rapamycin (mTOR) kinase. Previous studies with weekly temsirolimus at a dose of 250mg demonstrated a 38% overall response rate in 35 patients (JCO 23 (23); 5347–56, 2005). Thrombocytopenia was frequently observed and was dose limiting. The current study tested whether low-doses (25mg) of temsirolimus could produce a similar overall response rate (ORR) with less toxicity. Methods: Eligible patients had biopsy proven cyclin D1 positive MCL and had relapsed or were refractory to therapy. Patients received temsirolimus 25mg IV weekly as a single agent. Patients were restaged after 1 cycle (4 doses), after 3 cycles, and every 3 cycles thereafter. Patients with a tumor response after 6 cycles were eligible to continue drug for a total of 12 or 2 cycles after complete remission (CR) and then were observed without maintenance. The goal was to achieve an ORR of at least 20%. Results: Twenty-nine patients were enrolled between March and August 2005. Twenty-two patients have completed therapy. One patient with a major protocol violation on cycle-1 and one ineligible patient were excluded, leaving 27 evaluable patients. The ORR was 41% (11/27), with 1 CR and 10 PRs. Early evaluation of TTP showed a median of 5.5 months (95% CI: 3.3–7.7) and the duration of response for the 11 responders was 6.2 months (95% CI: 3.6 to not yet reached). These results compare favorably with the 6.5 months and 6.9 months, respectively, found in previous trials that used 250 mg. The median dose delivered per month was 80 mg (range, 10–100 mg). Sixteen (59%) of patients required a dose reduction. The median time on treatment was 4.4 months (95% CI, 3.3–7.7). The incidence of grade 3 and 4 thrombocytopenia was 12% and 0%, respectively. One patient experienced grade 5 infection without neutropenia, which was considered unrelated to CCI-779. Conclusions: Single agent CCI-779 at a dose of 25mg has anti-tumor activity in relapsed MCL similar to the 250 mg dose. This study indicates that combinations of temsirolimus with other agents should be feasible. [Table: see text]

17505 Background: A previous trial of 2-CDA as a single agent for therapy of mantle cell lymphoma demonstrated this agent to be efficacious with an overall response rate of 81% (31% complete responses) (Blood 1999 Nov 15; 94:660a). A phase II study of the addition of rituximab to 2-CDA was conducted by the North Central Cancer Treatment Group based on improved outcomes achieved by the addition of rituximab to other regimens active in MCL. Methods: This one-stage phase II study was designed to determine the complete response (CR) or complete response/unconfirmed (CRu) rate. Central pathology confirmation of cyclin D1 positive mantle cell lymphoma was required. No previous therapy for lymphoma was allowed, with the exception of splenectomy. The shedule was rituximab 375 mg/m2 IV day 1; 2-CDA 5 mg/m2/d IV days 1–5 of a 4-week cycle. After 2 of the first 6 patients developed grade 4 neutropenia, subsequent patients received either pegfilgrastim or filgrastim support. Patients received 2–6 cycles of therapy, depending on response. Patients were required to achieve at least a PR after 2 cycles of therapy to continue on protocol therapy. Results: Patient characteristics of all 29 eligible pts: median age: 70 (range: 41–86); 21 male, 8 female; PS 0 (55.2%), PS 1 (41.4%), PS 2 (3.5%); stage II (6.9%), stage III (3.5%), stage IV (89.7%); prior splenectomy (20.7%). The only grade 4 adverse event occurring more than once was neutropenia (20.7%). One patient died of cerebral ischemia in the setting of pneumonia without neutropenia. Response has been determined in 26 pts with 50.0% (95% CI: 30.0–70.0%) achieving a CR, none of whom have relapsed to date. Three patients progressed early at 17, 45, and 46 days, two of whom have died, and a fourth relapsed day 222. 10 pts (34.0%) went on to receive further therapy off study, 5 in less than a PR after 2 cycles, 2 in PR after study therapy, and 1 who went off study for a rash. At last contact, 26 (89.7%) were alive (median follow-up 10.7 months; range: 1–28). Conclusions: Rituximab and cladribine were well tolerated for the treatment of MCL in a group including elderly patients. The response rate may have been underestimated due to the study design, which required at least a PR after 2 cycles to continue therapy. Despite this, 50% achieved a complete remission. [Table: see text]

3503 Background: The association between race & toxicity or response to systemic chemotherapy is poorly understood. We correlated relevent polymorphisms with toxicity & outcome data in AA & C patients (Pts) enrolled in N9741, a large randomized MCRC trial. Methods: Toxicity, response rate (RR), time to progression (TTP), overall survival (OS), & dose intensity (DI) were examined as a function of race in 1412 Pts enrolled on IFL, both full and reduced dose, FOLFOX, or IROX including 486 Pts with pharmacogenomic data. Accrual by race permitted comparison of C (n=1297) to AA (n=112). Results: C & AA were similar in disease extent, PS, gender, prior adjuvant treatment, and DI at cycles 1, 3, 6, or 12. The impact of race on RR, toxicity & the distribution of four relevent drug metabolism genotypes are in the table . AA had lower RR overall & in each treatment arm. Lower toxicity rates were seen in AA Pts, mainly due to less diarrhea, as measured by both CTC V2 & patient reported outcome data. These relationships were maintained in multivariate models adjusting for arm, age, gender, & PS. In these multivariate models, the odds ratio between RR and race was 1.72 (p=0.012) (29% AA vs 41% C) & for severe toxicity the odds ratio was 1.76 (p=0.006) (34% AA vs 48% C). Overall, race was not a significant predictor of TTP or OS (p > 0.50 for each). The hazard ratio comparing FOLFOX to IFL for C was 0.67 and for AA was 0.55. TTP for FOLFOX was superior to both IFL and IROX for both C & AA. Significant differences in pharmacogenetic variants were observed between C & AA, although the sample size for investigating the three-way combination of Rx, race, & pharmacogenomics is too small (36 AA) to draw definitive conclusions. Conclusions: It appears that AA have less toxicity & a lower RR than C when treated with standard MCRC regimens. Different frequencies of polymorphisms in genes relevent to drug metabolism may help explain these clinical differences. [Table: see text] [Table: see text]

8565 Background: Previous studies using low-dose (250 ug/dose) aerosolized sargramostim (granulocyte macrophage colony stimulating factor: aero-GM-CSF) for the treatment of metastatic melanoma, revealed anecdotal clinical responses that appeared to correlate with an increase in the number of tumor specific cytotoxic T lymphocytes (CTL) in blood. Herein, we address whether or not further dose escalation of aero-GM-CSF is safe, results in greater increase of melanoma specific CTLs, and affects clinical outcomes. Methods: A 5+5 dose escalation clinical trial was conducted to determine the dose of aero-GM-CSF that would increase in the frequency of peripheral blood melanoma specific CTLs in HLA-A2+ patients with metastatic melanoma to the lungs. Aero-GM-CSF was administered twice daily on days 1–7 and 15–21 of a 28 day cycle at doses of: 500, 750, 1,000, 1,250, 1,500, 1,750, and 2,000 ug per cohort. If at most 2 of 5 patients at a dose level reported a 5-fold increase in CTLs, dose escalation occurred. If not, 5 additional patients were treated at that dose. Dose escalation continued until =2 of 5 patients at a dose level developed severe toxicity, at least 7 of the 10 patients at a dose level reported a 5-fold increase in CTLs, or all dose levels were exhausted. Results: The study accrued 40 patients from August 2002 to July 2006. Four patients cancelled participation prior to treatment. One patient was replaced (500 ug) as he died within 13 days of registration. Among the 35 remaining patients, median age was 58 (23–84), 72% were male, and 72% had a PS=0. Dose escalation was not terminated due to toxicity. Toxicities = grade 3 (at least probably treatment related) included: grade 3 fatigue (1) at 1,000 ug; and grade 3 cough (1), and grade 4 dyspnea (1) at 1,750 ug. At the 2,000 ug dose, most patients (4 of 5) exhibited a greater than 2-fold increase in melanoma specific CTLs. Two of these patients remain on treatment: one with partial response at 14.0 months and the other with stable disease at 6.5 months. A 5-fold increase in tumor specific CTLs was not achieved in any patient. Conclusions: Aero-GM-CSF therapy administered at up to 2,000 ug/dose appears safe and seems to correlate with increased frequencies of tumor specific CTLs in a dose-dependent fashion. Further dose escalation followed by clinical efficacy testing is warranted. No significant financial relationships to disclose.

4067 Background: N9741 randomized 1691 patients (pts) to seven 5FU, Ox and Iri containing regimens for MCRC. After 20.4 months median follow-up, FOLFOX and IROX improved time to progression (TTP) and overall survival (OS) compared to IFL. Here we update OS and TTP, and report an analysis of factors prognostic of pt outcome. Methods: 5 yr OS and TTP were calculated by Kaplan-Meier per treatment (rx) arm. Pt factors [rx arm, age, gender, prior adjuvant rx, body mass index (BMI), performance status (PS), number of disease sites (#sites), neutrophil count (ANC), hemoglobin, platelets, bilirubin, alkaline phosphatase (ALK), aspartate aminotransferase (AST)] were assessed for univariate association with OS, TTP, response rate (RR), and any grade =3 toxicity. Associated factors were included in multivariate Cox and logistic regression models. Results: After a median follow-up of 4.3 yrs, FOLFOX treated pts were more likely to live 5 yrs, 9.2% versus 5.4% for IROX (p=.016) and 3.8% for IFL (p<.001). Median TTP was also significantly longer in the FOLFOX arm, 9.2 mo vs 6.5 mo for IROX (p=<.001) and 6.0 mo for IFL (p=<.001). The prognostic model found higher PS, ANC and ALK, and more disease sites were prognostic of worse OS (see table ). Age = 70 was associated with poorer survival (HR death 1.33, p=.03), but not TTP, RR, or grade =3 toxicity. FOLFOX rx was the most powerful prognostic factor for TTP and OS. The odds of grade =3 toxicity were significantly higher in FOLFOX treated pts (OR 1.65, p<.001) and lower in men (OR .63, p<.001). No significant interactions between rx arm and pt factors were present, suggesting no factor examined is predictive of rx-specific outcome. Conclusions: 9% 5 yr OS in MCRC pts treated with first-line FOLFOX sets a new benchmark. We confirmed pre-rx PS, WBC, and ALK are prognostic for OS, though FOLFOX rx was the strongest prognostic factor. No factor was associated with differential outcome or toxicity by rx arm, thus these factors cannot be used to guide rx selection. [Table: see text] [Table: see text]