scholarly journals Comparison of thalidomide and lenalidomide as therapy for myelofibrosis

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 899-902 ◽  
Author(s):  
Elias Jabbour ◽  
Deborah Thomas ◽  
Hagop Kantarjian ◽  
Lingsha Zhou ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Side Effects ◽  
Working Group ◽  
Performance Status ◽  
Single Agent ◽  
Response Duration ◽  
Phase 2 ◽  
Prednisone Therapy ◽  
International Working Group ◽  
Consecutive Phase

Abstract With the use of the International Working Group for Myelofibrosis Treatment and Research consensus criteria, we re-assessed the efficacy of thalidomide and lenalidomide in 125 patients with myelofibrosis treated in 3 consecutive phase 2 trials: 44 received single-agent thalidomide, 41 single-agent lenalidomide, and 40 a combination of lenalidomide plus prednisone. The thalidomide group included significantly more untreated patients and patients with performance status of 2. The Lenalidomide-based therapy produced higher efficacy (34%-38%) than thalidomide (16%; P = .06). Responses to thalidomide were seen within 3-15 weeks, whereas responses to the lenalidomide-based therapy were also seen after a prolonged course of therapy (range, 2-45 weeks). Lenalidomide plus prednisone therapy resulted in significantly longer response duration (median, 34 months) than single-agent lenalidomide or thalidomide (median, 7 and 13 months, respectively; P = .042). Fewer patients (P = .001) discontinued the lenalidomide plus prednisone therapy (13%) because of side effects then patients on single-agents therapy (32%-39%). In conclusion, the combination of lenalidomide plus prednisone appears to be more ef-fective and safer than single-agent thalidomide or lenalidomide.

Combination intraventricular chemotherapy for meningeal neoplasia.

1986 ◽  
Vol 4 (1) ◽  
pp. 68-73 ◽  
Author(s):  
L Giannone ◽  
F A Greco ◽  
J D Hainsworth
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Transitional Cell ◽  
Response Duration ◽  
Complete Response ◽  
Response To Therapy ◽  
Entire Group ◽  
Intraventricular Chemotherapy ◽  
Wbc Count

Twenty two patients with meningeal neoplasia were treated with biweekly combination intraventricular chemotherapy using methotrexate, cytosine arabinoside, and thiotepa. Patients with the following malignancies were included: breast cancer, ten patients; lung cancer, seven; non-Hodgkin's lymphoma, two; malignant melanoma, one; transitional cell carcinoma of the bladder, one; and malignant glioma, one. Eight of 22 patients (36%) had a Karnofsky performance status of less than 50%. Eleven of 22 patients received radiotherapy to symptomatic areas, and seven received systemic chemotherapy in addition to combination intraventricular therapy. Patients were evaluated for both toxicity and response to therapy. Myelosuppression was the major toxic condition and occurred in 17 of 22 patients (77%). Ten patients (45%) had a nadir WBC count of less than 1000/microL or a platelet count of less than 25,000/microL. No patient achieved a complete response (CR), although nine patients (41%) had partial responses (PRs) lasting 4 to 24 + weeks. Median survival for the entire group was 10 weeks (range, 6 to 24+ weeks). In this small group of patients, simultaneous triple-drug intraventricular chemotherapy caused unacceptable myelosuppression without increasing the response rate, response duration, or survival when compared with single-agent methotrexate and radiotherapy.

scholarly journals Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results of the Pivotal Phase II BELIEF (CLN-19) Study

2015 ◽  
Vol 33 (23) ◽  
pp. 2492-2499 ◽  
Author(s):  
Owen A. O'Connor ◽  
Steven Horwitz ◽  
Tamás Masszi ◽  
Achiel Van Hoof ◽  
Peter Brown ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Working Group ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Standard Of Care ◽  
Pivotal Phase ◽  
Overall Response ◽  
International Working Group

Purpose Peripheral T-cell lymphomas (PTCLs) represent a diverse group of non-Hodgkin lymphomas with a poor prognosis and no accepted standard of care for patients with relapsed or refractory disease. This study evaluated the efficacy and tolerability of belinostat, a novel histone deacetylase inhibitor, as a single agent in relapsed or refractory PTCL. Patients and Methods Patients with confirmed PTCL who experienced progression after ≥ one prior therapy received belinostat 1,000 mg/m2 as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary end point was overall response rate. Secondary end points included duration of response (DoR) and progression-free and overall survival. Results A total of 129 patients were enrolled, with a median of two prior systemic therapies. Overall response rate in the 120 evaluable patients was 25.8% (31 of 120), including 13 complete (10.8%) and 18 partial responses (15%). Median DoR by International Working Group criteria was 13.6 months, with the longest ongoing patient at ≥ 36 months. Median progression-free and overall survival were 1.6 and 7.9 months, respectively. Twelve of the enrolled patients underwent stem-cell transplantation after belinostat monotherapy. The most common grade 3 to 4 adverse events were anemia (10.8%), thrombocytopenia (7%), dyspnea (6.2%), and neutropenia (6.2%). Conclusion Monotherapy with belinostat produced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across the major subtypes, irrespective of number or type of prior therapies. These results have led to US Food and Drug Administration approval of belinostat for this indication.

Lumiliximab with fludarabine, cyclophosphamide, and rituximab (FCR) for patients with relapsed chronic lymphocytic leukemia (CLL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6597-6597 ◽  
Author(s):  
S. O’Brien ◽  
J. C. Byrd ◽  
T. J. Kipps ◽  
A. Forero-Torres ◽  
I. W. Flinn ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Open Label ◽  
Prior Therapy

6597 Background: Lumiliximab, an anti-CD23 monoclonal antibody, had pharmacologic activity and an outstanding safety profile in a recently completed phase 1, single-agent study. Based on evidence of clinical activity, favorable safety profile, and preclinical data suggesting synergy with both fludarabine and rituximab, we initiated a combination study of lumiliximab with FCR in previously treated patients. Methods: Patients ≥18 years of age with relapsed CD23+ B-cell CLL were eligible for this open-label, dose-escalation, phase 1/2 study. Sample size was planned for ≤37 patients. Patients received either 375 mg/m2 or 500 mg/m2 of lumiliximab in combination with each 28-day cycle of FCR for 6 cycles. Primary objectives were to determine the safety profile, recommended phase 2 dose, and clinical activity of lumiliximab with FCR. Results: Accrual began in June 2004; 30 of the 31 patients were enrolled by December 2005; data are available for 28 patients. No dose-limiting toxicity was noted in the phase 1 component (375 mg/m2 dose, n=3, and 500 mg/m2 dose, n=6) and 500 mg/m2 was chosen for the phase 2 dose. All enrolled patients had progressive, symptomatic CLL as defined by NCI criteria, median 2 prior treatments (range, 1 to 9), median age 58, 64% males, 96% WHO performance status of ≤1. Seventeen patients experienced CTC Grade 3 or 4 adverse events (hematologic toxicity typically associated with FCR). Sixteen patients completed ≥3 cycles of treatment and were evaluated for response using NCI-WG criteria: 7 (44%) patients with confirmed complete responses (CRs); 1 with unconfirmed CR (pending marrow confirmation), 3 with partial responses (PRs), 4 with PRs awaiting confirmation, and 1 with disease progression. Twelve patients are not yet evaluable for response. Conclusions: Lumiliximab in combination with FCR is well tolerated and may enhance the activity of FCR for treatment of patients with progressive CLL after prior therapy. [Table: see text]

Randomized phase 2 study of maintenance pemetrexed (Pem) versus observation (Obs) for patients (pts) with malignant pleural mesothelioma (MPM) without progression after first-line chemotherapy: Cancer and Leukemia Group B (CALGB) 30901 (Alliance).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8517-8517 ◽  
Author(s):  
Arkadiusz Z. Dudek ◽  
Xiaofei F. Wang ◽  
Lin Gu ◽  
Tom Stinchcombe ◽  
Robert Arthur Kratzke ◽  
...  
Keyword(s):  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Phase 2 ◽  
First Line ◽  
Efficacy Analysis ◽  
Phase 2 Trial ◽  
Group B ◽  
Line Chemotherapy ◽  
Randomized Phase 2

8517 Background: Standard front-line chemotherapy for advanced MPM is (Pem and a platinum; optimal treatment duration is unknown. We performed a randomized phase 2 trial (NCT01085630) to determine if continuation of single-agent Pem after 4-6 cycles of Pem-platinum would improve progression-free survival (PFS). Methods: Eligible pts had histologically confirmed unresectable MPM, and performance status (PS) 0-1. Pts with at least stable disease following 4-6 cycles of Pem-platinum were stratified by first-line regimen (cis- or carboplatin) and histology (epithelioid versus other) and randomized 1:1 to Obs or continuation of Pem until progression. The primary endpoint was PFS. We assumed that Obs produced a median (m) PFS of 3 months (mo) and Pem would yield a 100% improvement in mPFS to 6 mo; 60 eligible pts (30 per arm) were to be randomized. Results: 72 pts from 30 sites registered 12/10-6/16. The study closed early due to slow accrual once 53 pts were randomized; 49 eligible pts (22 Obs, 27 Pem) are included in the efficacy analysis. Pt characteristics (Obs/Pem): age: median (range) 70 (39-85)/70 (52-87); male 68%/78%; PS 0 27%/33%; epithelioid histology 77%/70%; first-line cisplatin 27%/26%. A median of 4 cycles of Pem (range 1-33) was delivered; 22% of pts required dose modification. mPFS was 3 mo on Obs and 3.4 mo on Pem (hazard ratio (HR) 0.99; 95% CI: 0.51-1.90; p=0.9733). Median overall survival (mOS) was 11.8 mo for Obs, and 16.3 mo for Pem (HR 0.86; 95% CI 0.44-1.71; p=0.6737). Toxicities ≥ grade 3 on Pem included anemia 8%, lymphopenia 8%, neutropenia 4%, and fatigue 4%; there were no grade 5 toxicities. A higher baseline level of serum mesothelin related peptide (SMRP) was associated with worse PFS (HR 1.861, p=0.049). Baseline osteopontin did not significantly affect PFS (p=0.3630). Conclusions: Although it was well tolerated, maintenance Pem following initial Pem/platinum doublet chemotherapy does not improve PFS in MPM patients. High baseline SMRP was associated with shorter PFS. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01085630.

Case series on the safety of mRNA COVID19 vaccines in cancer patients undergoing treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14562-e14562
Author(s):  
Faysal Haroun ◽  
Malak Alharbi ◽  
Alison Hong
Keyword(s):  
Side Effects ◽  
Cancer Therapy ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Single Agent ◽  
Case Series ◽  
Vaccine Uptake ◽  
Cancer Center ◽  
High Risk Population ◽  
Patients With Cancer

e14562 Background: Millions of vaccines have been administered since Emergency Use Authorization has been granted for two mRNA COVID-19 vaccines (mCV). The Center for Disease Control (CDC) and Prevention recommends that immunocompromised individuals with no contraindications to vaccines may receive an mCV. The CDC suggests that patients receiving cancer therapies should be consulted about the unknown vaccine safety profile and effectiveness. The American Society of Clinical Oncology recognizes that vaccine may reduce the risk of infection for individuals with cancer. Vaccine trials have not actively enrolled immunocompromised or patients on active cancer therapy; therefore, the potential side effects and efficacy of the mRNA vaccines in these individuals are unexplored. Per state guidelines, many patients with cancer undergoing treatment qualify for vaccination however current vaccine uptake in that population is unknown. Data in this specific high-risk population is needed to increase confidence in the vaccine. We explored adverse events (AE) to the mCV in a small cohort of patients undergoing cancer therapy. Methods: Our case series evaluated patients' tolerance to the voluntary but recommended 2 doses of the mCV while on chemotherapy (CX), checkpoint inhibitors (CPI) or tyrosine kinase inhibitors (TKI) at the George Washington University (GWU) Cancer Center in Washington DC. Patient chart review and phone interviews were conducted. Patients had independently signed up for the mCV at the GWU Hospital or through the DC Health Department. Patients were asked if they had experienced any of the commonly reported side effects listed by the CDC or others new symptoms receiving the vaccine. Results: 12 patients had voluntarily received the mCV, all patients were above the age of 65 with a mean age of 72 (66-85). ECOG performance status was 2 or above in 4 patients. 6 patients were receiving single agent CPI, 1 patient was on combination CX and CPI. 2 patients were on oral TKI for EGFR mutated lung cancer. 3 other patients were on combination CX with rituximab, ramucirumab or radiation. In the 2 patients on daily TKI, treatment was not interrupted for the mCV. In the 10 other patients, all but one patient received the mCV at least one week after the last therapy. Both mCV were tolerated without any life-threatening AE or hospitalization. Pain and swelling at the vaccine site were the most common local AE and reported in 7 patients. 6 patients reported systemic AE most commonly myalgia and headaches. Conclusions: This exploratory analysis in 12 patients with cancer undergoing treatment did not uncover any additional SE signals. Larger studies are needed to evaluate AE and efficacy and to guide recommendations for COVID19 vaccination in this patient population.

Results of a Randomized Phase 2 Study of Clofarabine Plus Cytarabine (CA) Vs Clofarabine Plus Idarubicin (CI) Vs Clofarabine, Idarubicin, Plus Cytarabine (CIA) as Salvage Therapy in Acute Myeloid Leukemia (AML).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 964-964 ◽  
Author(s):  
Stefan Faderl ◽  
Gautam Borthakur ◽  
Farhad Ravandi ◽  
Xuelin Huang ◽  
Miloslav Beran ◽  
...  
Keyword(s):  
Overall Survival ◽  
Salvage Therapy ◽  
Phase 1 ◽  
Single Agent ◽  
Response Duration ◽  
Infectious Complications ◽  
Dose Finding ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Randomized Phase 2

Abstract Clofarabine is a second-generation deoxyadenosine analog with activity in adult AML. To improve single agent activity, various combinations of clofarabine are being studied. In two dose-finding phase I studies, we have previously established the MTD and DLT of the CI and CIA combinations in AML salvage (Blood2006; 108: 51a). Here we report the outcome of a subsequent adaptively (Bayesian) randomized phase 2 study comparing the two anthracycline-containing combinations CI and CIA with CA. Eligible were patients (pts) for first salvage therapy with first relapse or primary refractory AML. Drug doses and schedules were as follows: CI - clofarabine 22.5 mg/m2 iv d 1–5 and idarubicin 10 mg/m2 iv d 1–3; CIA – clofarabine 22.5 mg/m2 iv d 1–5, idarubicin 6 mg/m2 iv d 1–3, cytarabine 0.75 g/m2 d 1–5; CA - clofarabine 40 mg/m2 iv d 1–5 and cytarabine 1g/m2 iv d 1–5. Up to 2 induction and 4 consolidation cycles were allowed. Eighty-five patients were enrolled of whom 80 are evaluable. Pretreatment characteristics were similar with respect to median age (CI 57 yrs [range 25–73], CIA 56 [21–81], CA 55 [39–73]), proportion of pts with secondary AML (CI 33%, CIA 28%, CA 29%), proportion of pts with primary refractory disease (CI 31%, CIA 50%, CA 41%), prior median CR duration (CI 6 mos [1–108], CIA 6 [1–18], CA 10 [2–27]), prior exposure to at least intermediate doses of cytarabine (CI 78%, CIA 63%, CA 65%), and proportion of pts with FLT3/ITD abnormalities (CI 25%, CIA 17%, CA 18%). Thirty-three pts received CI, 31 CIA, and 16 CA. Overall, 31 (39%) pts responded (28% CR, 9% CRp). No difference in response was observed according to treatment arm (CI - CR 27%, CRp 12%; CIA - CR 29%, CRp 13%; CA - CR 25%, CRp 6%). Median CR duration was 6.4 mos (0.2–18) with CI, and not reached (1–12+) with CIA and CA (0.3–24) (p=0.07). Overall survival was 5.5 mos (0.3–25.5+) for CI, 5.1 mos (0.4– 13.4+) for CIA, and 5.1 mos (0.4–27+) for CA (p=0.94). Adverse events were comparable to the preceding phase 1 studies and as have been described with clofarabine in the past. Induction deaths occurred in 6% (CI), 16% (CIA), and 25% (CA), respectively (p>.05), and were due to myelosuppression-associated infectious complications. In summary, the response rate of the clofarabine combinations in AML salvage is 39% (CR+CRp). Response duration and overall survival are not significantly different between the treatment arms.

Everolimus (E) and octreotid (O) in metastatic high-risk MEN IIb disease: A case report.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13565-e13565
Author(s):  
Antje Dresemann ◽  
Gregor Paul Dresemann
Keyword(s):  
Side Effects ◽  
High Risk ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Somatostatin Receptor ◽  
Single Agent ◽  
Additional Treatment ◽  
Pet Ct ◽  
And Performance ◽  
Ecog Ps

e13565 Background: Multiple endocrine neoplasia (MEN) type IIB is characterized by missense mutation in exon 16 of the RET-proto-onkogen. Malignant c-cell-(medullar)-carcinoma of the thyroid gland (MTC) is part of the disease. Prognostic factors for metastatic MTC (m-MTC) are tumor grading, vessel- and peri-neural infiltration, age and performance status (PS). Irradiation and chemotherapy have limited activity in m-MTC. Thyrosine-kinase inhibitors like vandetanib, sorafenib or sunitinib were not admitted in Germany in 2011, August. As mTor-pathway seems to play a role in m-MTC E was suggested to be a treatment alternative. In somatostatin receptor (SR) positive tumors O might be beneficial. Methods: In 2011, August, a 23 years old man presented with metastatic MEN IIB disease after palliative irradiation therapy. ECOG-PS was 2 to 3, Calcitonin was 3.615 pg/ml, CEA was 467 ng/ml. The patient (pt) had a non-resectable m-MTC, SR positive, with esophageal, pleural, tracheal and lymph node infiltration still with metabolic activity in PET-CT. Grading was G3 with strong vessel and peri-neural infiltration. Right adrenal tumor and tongue tumor were present. After written informed consent the pt started treatment with E 10 mg/day orally in 2011, November. A loperamide resistant diarrhea was treated with O 20 mg/4 weeks i. m. additionally since 2012, July. Results: During treatment with E Calcitonin and CEA levels continuously decreased and CT scans every 3 months demonstrated a continuous shrinkage of all tumor sites, especially after additional treatment with O, which also was associated with an improved PS. Since 2012, October, ECOG PS was 0 enabling the patient to go to work again. Since 2012, October no relevant treatment related side effects were present. Conclusions: E showed efficacy as single agent treatment in a young man with metastatic high risk MEN IIB disease, the addition of O seems to reduce side effects and to improve efficacy of single agent E in this case. Further investigation is needed to verify these results

A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2607-TPS2607
Author(s):  
Maxime Chenard-Poirier ◽  
Alvaro Henrique Ingles Garces ◽  
Robert Hugh Jones ◽  
Amy Quinton ◽  
Elizabeth R. Plummer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Advanced Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Cell Cycle Checkpoint ◽  
Phase 2 ◽  
Regulatory Review

TPS2607 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells and have utility as a monotherapy in a range of tumor indications. SRA737 is currently being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation, monotherapy study of SRA737 (NCT02797964). Methods: Up to 40 patients with advanced cancer will receive oral SRA737 administered daily on a 28-day schedule. For dose-escalation, an accelerated titration design with 100% dose escalation and single patient cohorts is allowed until Grade 2 related toxicity is observed, followed by a rolling-6 design. Dose expansion will include 6 patients with any solid tumor treated at the recommended Phase 2 dose (RP2D). Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of monotherapy SRA737 and to establish a RP2D. The PK profile and PD biomarkers will be investigated. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of indication specific expansion cohorts of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations such as gene mutations and amplifications/deletions, has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. The dose and schedule identified in this trial will inform the design and conduct of Phase 2 studies of SRA737 as a single agent and in combination with other targeted or immunomodulatory agents. Clinical trial information: NCT02797964.

scholarly journals Lenalidomide Plus R-CHOP (R2CHOP) in Patients with Follicular Lymphoma: Data from a Phase 1/2 Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5322-5322
Author(s):  
Ayed O. Ayed ◽  
Levi Pederson ◽  
William R. Macon ◽  
Betsy R. Laplant ◽  
Craig B. Reeder ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Phase 1 ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Phase 2 ◽  
Ecog Performance Status ◽  
Grade 3

Abstract Background Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma (NHL) with heterogeneous outcomes and remains largely incurable. Immunochemotherapy (IC) continues to be the standard therapy backbone in the frontline and relapsed settings, though novel agents are increasingly used and investigated. Lenalidomide is an immunomodulatory molecule with known single-agent activity in relapsed lymphoma. It is also active in the frontline setting and has been reported to be effective and tolerated in upfront combination regimens in FL (Fowler et al, Lancet Oncol. 2014, 15(12):1311-8). Here we report our experience with frontline use of R2CHOP (lenalidomide in combination with R-CHOP) in patients with FL. Methods A phase 1/2 study of R2CHOP was conducted in NHL patients with primarily diffuse large B-cell lymphoma (DLBCL). While the phase 2 study was focused on DLBCL patients, treatment-naive patients with stage II-IV, histologically-confirmed FL (grades 1, 2, and 3a) meeting criteria for therapy were eligible for the phase 1 part of the study. Additionally, FL patients were identified in the phase 2 portion of the study after central pathology review. These patients were allowed to complete therapy and were followed accordingly. Treatment consisted of 6 cycles of R2CHOP with lenalidomide given on days 1-10 and R-CHOP given in 21-day cycles. All patients received pegfilgrastim and aspirin (if not on anticoagulation) along with other supportive measures per provider discretion. Primary objectives were safety assessment and efficacy. Results Ten patients with FL (3 had grade 1, 3 had grade 2, and 4 had grade 3a) were enrolled in the R2CHOP phase 1/2 study at Mayo Clinic. One patient was in the phase 1 arm at dose level 2 (lenalidomide 20 mg/d) and 9 patients were in the phase 2 arm (lenalidomide 25 mg/d). The mean age was 60.8 years (range: 41-82). Eight out of ten patients were male; 5/10 had ECOG performance status of 0; 5/10 had an IPI score of intermediate or higher. All patients completed 6 cycles of planned treatment. One patient required lenalidomide dose adjustment due to toxicity. There were no lenalidomide dose interruptions. The overall response rate (ORR) was 100% and the complete response (CR) rate defined by PET imaging was 90%. Eight out of ten remain progression-free and 9/10 are alive at a median follow-up of 4.6 years (range: 2.1-5.3). Estimated progression-free survival (PFS) at 5 years was 79% (95% CI: 56-100%). The main toxicity was reversible myelosuppression with 80% treatment-related hematologic grade 3 or higher adverse events (AEs) (leukopenia 80%, neutropenia 80%, thrombocytopenia 40%, anemia 20%, transaminitis 20%). Rate of nonhematologic grade 3 or higher AEs was 20% (fatigue 10%, pneumonia 10%). Conclusions Frontline therapy with R2CHOP in patients with untreated FL appears to be effective and associated with acceptable toxicity. The observed PET-based CR rate and PFS were promising in this cohort. Whether R2CHOP is superior to lenalidomide/rituximab alone or standard bendamustine/rituximab will require randomized studies. Figure Estimated PFS in FL patients treated with upfront R2CHOP. Figure. Estimated PFS in FL patients treated with upfront R2CHOP. Disclosures Reeder: Celgene: Research Funding; Novartis: Research Funding; BMS: Research Funding; Millennium: Research Funding. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; karyopharm: Honoraria; medscape: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Nowakowski:Bayer: Consultancy, Research Funding; Morphosys: Research Funding; Celgene: Research Funding.

Combination Targeted Therapy With Sorafenib and Bevacizumab Results in Enhanced Toxicity and Antitumor Activity

2008 ◽  
Vol 26 (22) ◽  
pp. 3709-3714 ◽  
Author(s):  
Nilofer S. Azad ◽  
Edwin M. Posadas ◽  
Virginia E. Kwitkowski ◽  
Seth M. Steinberg ◽  
Lokesh Jain ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Group Performance ◽  
Performance Status ◽  
Cell Cancer ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Response Duration ◽  
Clinical Activity ◽  
Therapeutic Effects ◽  
Vegf Receptor

PurposeSorafenib inhibits Raf kinase and vascular endothelial growth factor (VEGF) receptor. Bevacizumab is a monoclonal antibody targeted against VEGF. We hypothesized that the complementary inhibition of VEGF signaling would have synergistic therapeutic effects.Patients and MethodsPatients had advanced solid tumors, Eastern Cooperative Oncology Group performance status of 0 to 1, and good end-organ function. A phase I dose-escalation trial of sorafenib and bevacizumab was initiated at below-recommended single-agent doses because of possible overlapping toxicity: sorafenib 200 mg orally twice daily and bevacizumab intravenously at 5 mg/kg (dose level [DL] 1) or 10 mg/kg (DL2) every 2 weeks. Additional patients were enrolled at the maximum-tolerated dose (MTD).ResultsThirty-nine patients were treated. DL1 was the MTD and administered in cohort 2 (N = 27). Dose-limiting toxicity in DL2 was grade 3 proteinuria and thrombocytopenia. Adverse events included hypertension, hand-foot syndrome, diarrhea, transaminitis, and fatigue. Partial responses (PRs) were seen in six (43%) of 13 patients with ovarian cancer (response duration range, 4 to 22+ months) and one of three patients with renal cell cancer (response duration, 14 months). PR or disease stabilization ≥ 4 months (median, 6 months; range, 4 to 22+ months) was seen in 22 (59%) of 37 assessable patients. The majority (74%) required sorafenib dose reduction to 200 mg/d at a median of four cycles (range, one to 12 cycles).ConclusionCombination therapy with sorafenib and bevacizumab has promising clinical activity, especially in patients with ovarian cancer. The rapidity and frequency of sorafenib dose reductions indicates that sorafenib at 200 mg twice daily with bevacizumab 5 mg/kg every 2 weeks may not be tolerable long term, and alternate sorafenib dosing schedules should be explored.

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