A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.     

Early versus late intensification for patients with high‐risk Hodgkin lymphoma—3 Cycles of intensive chemotherapy plus low‐dose lymph node radiation therapy versus 4 cycles of combined doxorubicin,bleomycin, vinblastine,and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation

BACKGROUND.

The 5‐year freedom from treatment failure (FFTF) rate, with treatment failure defined as the lack of post‐treatment complete remission (CR), recurrence, or death, ranges from 60% to 70% after 6 to 8 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), which is the reference treatment for patients with advanced Hodgkin lymphoma (HL). In this randomized, phase 2 study, the authors tested 2 intensive chemotherapy regimens in 158 patients with clinical stage (CS) IIB through IV HL accompanied by high‐risk factors who were recruited between May 1997 and December 2004.

METHODS.

High‐risk CS IIB, III, and IV were defined by the presence of ≥5 involved lymphoid areas, and/or a mediastinal mass ratio ≥0.45, and/or ≥2 extra lymph node sites affected by the disease (for CS IV). In Arm V, 82 patients received 3 courses of combined vindesine (5 mg/m²), doxorubicin (99 mg/m²), carmustine (140 mg/m²), etoposide (600 mg/m²), and methylprednisolone (600 mg/m²) (VABEM) followed by low‐dose lymph node irradiation. In Arm A, 76 patients received 4 cycles of ABVD followed by myeloablative combined carmustine (300 mg/m²), etoposide (800 mg/m²), cytarabine (1600 mg/m²), and melphalan (140 mg/m²) and underwent autologous stem cell transplantation.

RESULTS.

After 3 cycles of VABEM, the CR rate was 89% versus 60% after 4 cycles of ABVD. However, after the completion of treatment, the CR rates for Arms V and A were similar (89% and 88%, respectively). The 5‐year FFTF rates for Arms V and A also were similar (79% and 75%, respectively) along with the 5‐year overall survival rates (87% and 86%, respectively).

CONCLUSIONS.

Early intensification (Arm V) and late intensification (Arm A) were equally effective for treating patients with high‐risk/advanced HL. Cancer 2008. © 2008 American Cancer Society.     

A randomized phase 2 trial of a preparative regimen of bortezomib, high-dose melphalan, arsenic trioxide, and ascorbic acid

BACKGROUND:

Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and it has synergistic activity with melphalan. The authors of this report conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan.

METHODS:

Among 60 patients who enrolled between October 2006 and September 2007, 58 patients underwent autologous transplantation with a preparative regimen of melphalan 200 mg/m² intravenously, AA 1000 mg daily intravenously for 7 days, and ATO 0.25 mg/kg intravenously for 7 days. Patients were randomized to receive no bortezomib (Group 1), bortezomib 1 mg/m² × 3 doses (Group 2), and bortezomib 1.5 mg/m² × 3 doses (Group 3). Primary endpoints were complete response (CR), grade IV toxicity, and 90‐day treatment‐related mortality (TRM). Secondary endpoints were progression‐free survival (PFS) and overall survival (OS).

RESULTS:

The median follow‐up of all surviving patients was 36 months (range, 20‐43 months). The CR rates in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. Grade 3 and 4 nonhematologic toxicities and TRM were comparable. The median OS was not reached in the groups, whereas the median PFS in Groups 1, 2, and 3 was 17.8 months, 17.4 months, and 20.7 months, respectively. PFS and OS were significantly shorter in patients who had high‐risk cytogenetics (P = .016 and P = .0001, respectively) and relapsed disease (P = .0001 and P = .0001, respectively) regardless of the treatment group.

CONCLUSIONS:

Adding bortezomib to a preparative regimen of ATO, AA, and high‐dose melphalan was safe and well tolerated in patients with multiple myeloma. There was no significant improvement in the CR rate, PFS, or OS in the bortezomib groups. Cancer 2012;. © 2011 American Cancer Society.     

Phase I study of proteasome inhibitor bortezomib plus CHOP in patients with advanced,aggressive T-cell or NK/T-cell lymphoma

The aim of the study was to determine the maximum tolerated dose (MTD) and safety of the combination of bortezomib and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) as first-line therapy in advanced, aggressive T-cell lymphoma. Patients received increasing doses of bortezomib on days 1 and 8 (weekly schedule, 1.0, 1.3, and 1.6 mg/m²/dose) in addition to 750 mg/m² cyclophosphamide, 50 mg/m² doxorubicin, 1.4 mg/m² vincristine on day 1 and 100 mg/day prednisolone on days 1 to 5, every 3 weeks. Six cycles of therapy administered every 21 days were planned. Thirteen patients, who had stage III/IV chemonaive aggressive T-cell lymphoma, received a total of 55 cycles of treatment. One patient experienced hematologic dose-limiting toxicity (grade 4 neutropenia associated with febrile episode) at the 1.0 mg/m²/dose of bortezomib. There was no dose-limiting non-hematologic toxicity. The MTD was not reached at 1.6 mg/m² dose level of bortezomib. The overall complete remission rate in all patients was 61.5% (95% confidence interval = 31.6–86.1). Bortezomib can be safely combined with CHOP chemotherapy and constitutes an active regimen in advanced-stage, aggressive T-cell lymphoma patients. The recommended dose for subsequent phase II studies of bortezomib plus CHOP is 1.6 mg/m²/dose of bortezomib on days 1 and 8 every 3 weeks as first-line treatment.     

A Phase II Study of Capecitabine, Oxaliplatin, and Cetuximab with or Without Bevacizumab as Frontline Therapy for Metastatic Colorectal Cancer. A Fox Chase Extramural Research Study

Objectives

Dual inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) demonstrated initial promise in clinical trials. This phase II study tested the efficacy and safety of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as first-line treatment for metastatic colorectal cancer patients.

Methods

Patients were randomized to receive capecitabine 850 mg/m² PO twice daily for 14 days, oxaliplatin 130 mg/m² IV day 1, and cetuximab 400 mg/m² IV loading dose followed by 250 mg/m² IV days 1, 8, and 15 with (Arm A) or without (Arm B) bevacizumab 7.5 mg/kg IV day 1 every 21 days. Tumor samples were collected and retrospectively analyzed for KRAS mutation status. The primary endpoint was response rate, with time to progression (TTP) and overall survival (OS) as secondary objectives.

Results

Twenty-three patients (12 in Arm A, 11 in Arm B) were enrolled onto the study. Median follow-up was 25.9 months. Both treatments were well tolerated, with expected higher rates of grade 1/2 hypertension and bleeding in Arm A. The overall response rate was 54% (36.4% in Arm A and 72.7% in Arm B). Median time to progression was 8.7 months in Arm A and 14.4 months in Arm B. The median survival was 18.0 months in Arm A and 42.5 months in Arm B. The study was prematurely terminated after other studies reported inferior outcomes with dual antibody therapy.

Conclusions

Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.     

Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation

BACKGROUND:

Indolent nonfollicular non‐Hodgkin B‐cell lymphomas (INFLs) are clonal mature B‐cell proliferations for which treatment has not been defined to date.

METHODS:

In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first‐line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m² intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m² intravenously on days 2‐4, cyclophosphamide 250 mg/m² intravenously on Days 2‐4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m² intravenously on day 1) every 2 months for responders.

RESULTS:

Forty‐seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow‐up of 40.9 months, the failure‐free survival and progression‐free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients.

CONCLUSIONS:

FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity. Cancer 2012. © 2011 American Cancer Society.     

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer

Purpose

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer.

Methods

Patients received continuous, once-daily oral doses of cediranib 20?mg in combination with either cisplatin (60?mg/m² iv day 1) plus S-1 (40?C60?mg bid, days 1?C21) every 5?weeks for a maximum of eight cycles [Arm A]; or cisplatin (80?mg/m² iv, day 1) plus capecitabine (1,000?mg/m² bid, days 1?C14) every 3?weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21?days of cycle 1.

Results

Fourteen patients (Arm A, n?=?6; Arm B, n?=?8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n?=?13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n?=?1; Arm B, n?=?2) partial responses that were ongoing at data cut-off.

Conclusions

Cediranib 20?mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.     

Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma

BACKGROUND:

In vitro studies in mantle cell lymphoma (MCL) cell lines and patient‐derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R‐bortezomib) compared with single‐agent bortezomib. Therefore, the authors of this report evaluated R‐bortezomib in a preclinical model and in a phase 2 clinical trial.

METHODS:

A Hu‐MCL‐severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R‐bortezomib, bortezomib, or rituximab. Twenty‐five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m² rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m² bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1‐5 cycles).

RESULTS:

R‐bortezomib resulted in a statistically significant improvement in overall survival in Hu‐MCL‐SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2‐year progression‐free survival (PFS) rate was 24% (95% confidence interval [CI], 10%‐53%) in all patients and 60% (95% CI, 20%‐85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R‐bortezomib compared with HH and RR homozygotes.

CONCLUSIONS:

R‐bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination. Cancer 2011. © 2010 American Cancer Society.     

Bortezomib,thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

BACKGROUND:

This single‐center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT).

METHODS:

Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3‐week cycles of bortezomib 1.3 mg/m² on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte‐colony–stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria.

RESULTS:

Review of medical records identified 44 eligible patients (34 patients who were treated in the front‐line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (≥VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front‐line patients, the ORR was 94%, which included a 56% ≥VGPR rate (24% sCR/CR). The median CD34‐positive stem cell collection was 10.67 × 10⁶/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% ≥VGPR rate (53% sCR/CR). Among all 44 patients, the median progression‐free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow‐up of 25 months, and the 2‐year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2‐year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis.

CONCLUSIONS:

BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long‐term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.     

Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma

BACKGROUND.

Relapsed or refractory mantle cell lymphoma has a very poor prognosis. The authors evaluated the response rates and survival times of patients treated with an intense regimen known to be effective against untreated aggressive mantle cell lymphoma: rituximab plus hyper‐CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab plus methotrexate‐cytarabine.

METHODS.

In this prospective, open‐label, phase 2 study, patients received this combination for 6 to 8 cycles. Twenty‐nine patients were evaluable for response.

RESULTS.

The median number of cycles received was 5 (range, 1‐7 cycles), and the overall response rate was 93% (45% complete response [CR] or CR unconfirmed [CRu] and 48% partial response [PR]). All 5 patients previously resistant to treatment had a response (1 CR, 4 PR), and both patients whose disease did not change in response to prior therapy had PRs. Toxic events occurring in response to the 104 cycles given included neutropenic fever (11%), grade 3 or 4 neutropenia (74%), and grade 3 or 4 thrombocytopenia (63%). There were no deaths from toxicity. At a median follow‐up of 40 months (range, 5‐48 months), the median failure‐free survival time was 11 months with no plateau in the survival curve.

CONCLUSIONS.

This combination chemotherapy was effective for refractory/relapsed mantle cell lymphoma. Cancer 2008. © 2008 American Cancer Society.     

A phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303)

BACKGROUND:

Bortezomib, an inhibitor of the 26S proteasome and NF‐κB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin.

METHODS:

Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0‐2, and ejection fraction within normal limits. Patients with stable disease for ≥9 months were excluded. Patients received bortezomib 1.3 mg/m² by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m² IV on Days 1 and 8 was added at the time of progression.

RESULTS:

Twenty‐five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single‐agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression‐free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3‐4 neutropenia (n = 3) and grade 3 anorexia (n = 2).

CONCLUSIONS:

Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC. Cancer 2011. © 2011 American Cancer Society.     

A study of paclitaxel,carboplatin, and bortezomib in the treatment of metastatic malignant melanoma

BACKGROUND:

Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3‐drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma).

METHODS:

A 2‐stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3‐agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m² intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m²; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21‐day cycle. The primary endpoint of this trial was tumor response rate (TRR).

RESULTS:

Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1‐7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade ≥3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression‐free survival was 3.2 months, and the median overall survival was 7.0 months.

CONCLUSIONS:

Due to insufficient clinical efficacy, this trial did not proceed to second‐stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity. Cancer 2010. © 2010 American Cancer Society.     

Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma

BACKGROUND:

Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R‐EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)‐associated, aggressive B‐cell, non‐Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.

METHODS:

The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV‐associated NHL who received either R‐CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R‐EPOCH (n = 51; AMC034). Age‐adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R‐CHOP vs R‐EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event‐free survival (EFS) and overall survival (OS).

RESULTS:

Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R‐EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment‐associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01).

CONCLUSIONS:

The current analysis provided additional level 2 evidence supporting the use of concurrent R‐EPOCH in patients with HIV‐associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R‐EPOCH with R‐CHOP in immunocompetent patients with diffuse large B‐cell lymphoma (National Clinical Trial no. NCT00118209). Cancer 2012. © 2011 American Cancer Society.     

A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome

BACKGROUND:

The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndrome.

METHODS:

Induction consisted of idarubicin 12 mg/m² a day on days 1‐3, cytarabine 1.5 g/m² intravenously continuously daily on days 1‐4 (days 1‐3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m² a day on days 1‐2, cytarabine 0.75 g/m² a day on days 1‐3, and tipifarnib 300 mg twice a day for 14 days every 4‐6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4‐6 weeks was continued for 6 months.

RESULTS:

With a median follow‐up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.

CONCLUSIONS:

The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor‐risk AML. Cancer 2011. © 2010 American Cancer Society.     

Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: Efficacy and safety outcomes of a randomized,multi-center phase II study investigating

Background

Modest benefits from concurrent chemoradiotherapy in patients with locally advanced NSCLC warrant further clinical investigations to identify more effective treatment regimens. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. We report on the safety and efficacy of the combination of daily dose Cisplatin and concurrent radiotherapy with or without weekly Cetuximab.

Patients and methods

Patients received high dose accelerated radiotherapy (66 Gy in 24 fractions) and concurrent daily Cisplatin (6 mg/m²) without (Arm A) or with (Arm B) weekly Cetuximab (400 mg/m² loading dose one week prior to radiotherapy followed by weekly 250 mg/m²). The primary endpoint of the trial was objective local control rate (OLCR) determined at 6–8 weeks after treatment. Toxicity was reported as well.

Results

Between February 2009 and May 2011, 102 patients were randomized. Median follow up was 29 months. The OLCR was 84% in Arm A and 92% in Arm B (p = 0.36). The one-year local progression free interval (LPFI) and overall survival (OS) were 69% and 82% for Arm A and 73% and 71% for Arm B, respectively (LPFI p = 0.39; OS p = 0.99). Toxicity compared equally between both groups.

Conclusion

The addition of Cetuximab to radiotherapy and concurrent Cisplatin did not improve disease control in patients with locally advanced NSCLC but increased treatment related toxicity.     

Efficacy and safety of the combination of rituximab,fludarabine, and mitoxantrone for rituximab‐naive,recurrent/refractory follicular non‐Hodgkin lymphoma with high tumor burden

BACKGROUND:

This phase 2 trial was undertaken to evaluate the efficacy and safety of rituximab combined with intravenous fludarabine and mitoxantrone (R‐FM) for patients with recurrent/refractory follicular lymphoma who had high tumor burden according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.

METHODS:

Fifty patients were enrolled who had received a maximum of 2 previous regimens, including 1 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)/CHOP‐like regimen but no previous exposure to rituximab, fludarabine, or mitoxantrone. At baseline, 58% of patients had bulky disease (lesion >7cm), 56% had high‐risk Follicular Lymphoma International Prognostic Index (FLIPI) scores (range, 3‐5), and 22% were refractory. Treatment consisted of 4 courses of R‐FM (rituximab 375 mg/m² intravenously on Day 1, fludarabine 25 mg/m² intravenously on Days 2 through 4, and mitoxantrone 10 mg/m² intravenously on Day 2, recycling at Day 28) and consolidation with 2 courses of fludarabine and mitoxantrone (the same regimen without rituximab).

RESULTS:

The best response (84% overall response rate including 68% complete response/complete response unconfirmed) was achieved after 4 courses of R‐FM. Response rates were high regardless of age, refractoriness to last previous therapy, and FLIPI score. After a median follow‐up of 4 years, the 3‐year progression‐free survival rate was 47%, the event‐free survival rate was 41%, and the 3‐year overall survival rate was 66%. Grade ≥3 neutropenia and infections were the most common toxicities and occurred in 72% and 14% of patients, respectively.

CONCLUSIONS:

Cytoreduction with 4 courses of R‐FM was safe and highly efficient in patients with recurrent/refractory follicular lymphoma who had high tumor burden; however, better consolidation than FM is needed to further improve outcome. Cancer 2010. © 2010 American Cancer Society.     

Treatment of myelodysplastic syndrome with 2 schedules and doses of oral topotecan

BACKGROUD:

The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS).

METHODS:

Patients with previously untreated primary or therapy‐related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if they were dependent on erythrocyte transfusion, had a platelet count <50,000/μL, or had an absolute neutrophil count <1000/μL with a recent infection that required antibiotics. Patients were randomized to receive oral topotecan either at a dose of 1.2 mg/m² twice daily for 5 days (Arm A) or once daily for 10 days (Arm B) repeated every 21 days for at least 2 cycles. Responding patients continued until they developed disease progression or unacceptable toxicity or until they had received 2 cycles beyond a complete response.

RESULTS:

Ninety patients received treatment, including 46 patients on Arm A and 44 patients on Arm B. Partial responses with improvement in all 3 cell lines occurred in 6 patients (7%), and hematologic improvement (in 1 or 2 cell lines) was observed in 21 patients (23%), for an overall response rate of 30%. Response duration was longer on Arm A (23 months vs 14 months; P = .02). Seven of 14 patients with chronic myelomonocytic leukemia responded. There were 8 treatment‐related deaths from infection (6 deaths) and bleeding (2 deaths). Diarrhea was the most frequent nonhematologic toxicity (grade 3, 11%; grade 4, 2%; grading determined according to the National Cancer Institute Comman Toxicity Criteria v.2.0).

CONCLUSIONS:

Oral topotecan in the dose and schedules evaluated in this trial demonstrated only a modest response rate with a troublesome toxicity profile in the treatment of MDS. Cancer 2009. © 2008 American Cancer Society.     

Prognostic value of MYC rearrangement in cases of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

BACKGROUND:

B‐cell lymphoma, Unclassifiable with features intermediate between diffuse large B‐cell lymphoma (DLBCL) and Burkitt lymphoma, for convenience referred to here as unclassifiable B‐cell lymphoma, is a category in the 2008 World Health Organization system used for a group of histologically aggressive neoplasms that are difficult to classify definitively. Currently, there is no established standard therapy for these neoplasms.

METHODS:

The authors assessed MYC status and correlated it with treatment response and outcome in a group of 52 patients with unclassifiable B‐cell lymphoma treated with either a standard DLBCL regimen (R‐CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone‐related therapy]) or more intensive regimens, such as R‐hyper‐CVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high‐dose methotrexate and cytarabine). The regimens were selected by the treating clinicians based on the overall clinical and pathological findings.

RESULTS:

Thirty (58%) unclassifiable B‐cell lymphomas had MYC abnormalities (MYC⁺) including 27 with rearrangement, 2 with amplification, and 1 with both. The MYC⁺ and MYC^? groups were similar in their age distribution and International Prognostic Index scores. Progression‐free survival of patients with MYC⁺ unclassifiable B‐cell lymphoma treated initially with R‐CHOP was significantly worse than patients treated with R‐hyper‐CVAD (P = .0358). In contrast, for the MYC^? unclassifiable B‐cell lymphoma group, some patients responded to R‐CHOP, and others were refractory to R‐hyper‐CVAD.

CONCLUSIONS:

MYC aberrations are common in unclassifiable B‐cell lymphoma. The presence of MYC aberrations identifies a patient subset that requires more aggressive therapy than R‐CHOP. In contrast, MYC^? unclassifiable B‐cell lymphoma patients responded variably to either R‐CHOP or aggressive therapy, and the latter showed no survival advantage. Cancer 2011;. © 2011 American Cancer Society.     

A phase 2 trial of induction nab‐paclitaxel and cetuximab given with cisplatin and 5‐fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck

BACKGROUND:

Complete response (CR) at the primary tumor site as assessed by clinical examination following induction chemotherapy with PF (cisp latin and 5‐f luorouracil [5‐FU]) is a favorable predictive factor for overall survival and disease control in patients with locally advanced squamous cell carcinoma of the head and neck. In most series, the rate of CR at the primary site after induction PF was 20% to 30%. This study evaluated the efficacy and feasibility of induction na b‐paclitaxel and c etuximab given with PF (ACPF) followed by definitive chemoradiation (CRT) in a phase 2 trial.

METHODS:

Patients with squamous cell carcinoma of the head and neck were treated with ACPF (nab‐paclitaxel 100 mg/m²/week; cetuximab 250 mg/m²/week; cisplatin 75 mg/m² on day 1; 5‐FU 750 mg/m²/day on days 1 through 3) every 21 days for 3 cycles followed by CRT (cisplatin 100 mg/m² on days 1, 22, and 43 of radiation therapy [RT]). CR at the primary tumor site after 2 cycles of ACPF was the primary endpoint.

RESULTS:

Thirty patients were enrolled, of which 22 (73%) had large (T3/T4) primary tumors. The CR rate at the primary tumor site after 2 cycles of ACPF was 53% and the overall response rate was 100%. Twenty‐nine (96%) patients completed 3 cycles of ACPF, 26 (90%) completed definitive RT per protocol, and 22 of the 27 evaluable patients (81%) received > 2 of the 3 planned doses of cisplatin with RT. The estimated 2‐year overall and progression‐free survival rates were 84% and 65%, respectively.

CONCLUSIONS:

Induction ACPF resulted in a high CR rate (53%) at the primary tumor site even in large tumors and did not adversely affect delivery of definitive CRT. Further investigation of ACPF is warranted. Cancer 2013. © 2012 American Cancer Society.     

Burkitt post-transplantation lymphoma in adult solid organ transplant recipients: Sequential immunochemotherapy with rituximab (R) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP is safe and effective in an analysis of 8 patients

BACKGROUND:

Burkitt lymphoma post‐transplantation lymphoproliferative disorder (Burkitt‐PTLD) is a rare form of monomorphic B‐cell PTLD for which no standard treatment has been established. Currently, the treatment of Burkitt lymphoma outside the post‐transplantation setting involves high doses of alkylating agents, frequent dosing, and intrathecal and/or systemic central nervous system prophylaxis. In PTLD, however, such protocols are associated with considerable toxicity and mortality.

METHODS:

The authors present a retrospective series of 8 adult patients with Burkitt‐PTLD. Six patients were reported to the prospective German PTLD registry or were enrolled in the PTLD‐1 trial, and 2 patients had received treatment before 2000, thus allowing for comparison with the pre‐rituximab era.

RESULTS:

Seven of the 8 patients were men. The median age at presentation was 38 years, and the median time since transplantation was 5.7 years. Five of 8 patients had histologically established, Epstein‐Barr virus‐associated disease, and 7 of 7 patients were positive for a MYC translocation. Five of 8 patients received sequential immunochemotherapy (4 courses of rituximab [R] followed by 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] or R plus CHOP [R‐CHOP]). In this group, 5 of 5 patients reached complete remission (CR), and their overall survival (OS) was significantly longer (P = .008) compared with the OS for 2 of 8 patients who received first‐line CHOP and did not respond. One of 8 patients (who had stage IV disease with meningiosis) received combination therapy (cyclophosphamide pretreatment, rituximab, intrathecal chemotherapy, whole‐brain irradiation, and radioimmunotherapy) and reached CR. Overall, 6 of 8 patients reached CR; and, after a median follow‐up of 4.7 years (range, 1.7‐4.8 years), the median OS was 36.7 months. There was no treatment‐related mortality under first‐line therapy.

CONCLUSIONS:

In the largest adult case series in Burkitt‐PTLD to date, sequential immunochemotherapy with rituximab followed by standard CHOP or R‐CHOP was a both safe and effective treatment. Cancer 2012. © 2012 American Cancer Society.