Phase II study of AZD2171 for the treatment of patients with myelodysplastic syndromes.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6570-6570
Author(s):  
Shannon Eileen O'Mahar ◽  
Alcee Jumonville ◽  
Patrick J. Flynn ◽  
Alvaro Moreno-Aspitia ◽  
Charles Erlichman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Prior Therapy ◽  
Starting Dose ◽  
Orally Bioavailable ◽  
Grade 3 ◽  
Endothelial Growth Factor

6570 Background: Inhibition of vascular endothelial growth factor receptors (VEGFR) can block growth and trigger apoptosis in neoplastic cells. AZD2171 (cediranib) is a highly potent, orally bioavailable, VEGFR-1/2 inhibitor. We conducted a phase II study of the efficacy of AZD2171 for the treatment of MDS. Methods: Adults with MDS (IPSS Int-2 or High) were eligible if they exhibited adequate organ function and ECOG 0-2. The primary endpoint was proportion of responses according to the IWG criteria assessed at one and every 3 months. Prior investigation of cediranib at 45 mg daily in patients with acute leukemia demonstrated toxicity concerns and therefore, the starting dose of this study was lowered to 30 mg daily. Results: A total of 16 pts with MDS (median age 73 years) were enrolled at a 30 mg starting dose, and all were evaluable. Median baseline marrow blasts were 12.0 % (range 2-18); 3 pts (18.8 %) had low, 6 (37.5 %) intermediate, and 7 (43.8 %) had high risk cytogenetics. Prior therapy included azacitidine (n=7), decitabine (n=2), cytarabine (n=2), erythropoietin-stimulating agents (ESAs) (n=2), lenalidomide (n=1), or none (n=6). Patients were treated for a median of two 28-day cycles (range 1 to 11). There were no confirmed responses. Patients with baseline blasts > 5% showed no significant reduction in the blast count at 4 and 12 weeks. Median OS was 4.7 mo (95% CI: 2.6 – 11.6). Median TTP was 3.8 mo (95% CI: 1.7 – 10.8). Grade 4 hematological adverse events at least possibly related to cediranib were neutropenia (n=2) and thrombocytopenia (n=4). Grade 3 hematological adverse events at least possibly related to study treatment included: neutropenia (n=3), thrombocytopenia (n=2), and anemia (n=2). Grade 3 non-hematological adverse events included fatigue (n=4), dyspnea (n=3), dehydration (n=2), diarrhea (n=2), nausea (n=2), asthenia (n=1), and hypertension (n=1). Hypertension and proteinuria was uncommon with the 30 mg/day dose. Conclusions: With no confirmed response from 16 patients, cediranib was determined to be ineffective at a dose of 30 mg daily in our patient population. Supported by NCI N01-CM62205, NCI P30-CA014520 and the UW Carbone Comprehensive Cancer Center.

A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4523-4523 ◽  
Author(s):  
Karen W.L. Yee ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
Farhad Ravandi-Kashani ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Blast Crisis ◽  
Single Agent ◽  
Mammalian Target Of Rapamycin ◽  
Median Number ◽  
Prior Therapy ◽  
Flat Dose ◽  
Grade 3

Abstract Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.

Phase II Study of Thalidomide in Escalating Doses for Follicular (F-NHL) and Small Lymphocytic Lymphoma (Sll): CALGB Study 50002.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3284-3284 ◽  
Author(s):  
David L. Grinblatt ◽  
Jeffrey Johnson ◽  
Donna Niedzwicki ◽  
David A. Rizzieri ◽  
Nancy Bartlett ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Phase Ii ◽  
Performance Status ◽  
Sensory Neuropathy ◽  
Complete Response ◽  
Lymph Node Biopsy ◽  
Prior Therapy ◽  
Median Daily Dose ◽  
Grade 3

Abstract Background: Thalidomide has marked activity in both untreated and heavily pretreated myeloma. Its activity in part is believed to be due to inhibition of bFGF and VEGF induced angiogenesis. Elevated levels of bFGF in serum and urine have correlated with decreased survival in lymphoma possibly through up-regulation of BCL-2. Methods: 25 patients (pts) with previously treated F-NHL and SLL were registered and treated on this multi-institutional study from July 2001–April 2004 to evaluate the efficacy and safety of oral thalidomide in this patient group. Pts had B-cell SLL (7: 36.8%), F-NHL grade 1 (7: 36.8%), grade 2 (3: 15.8%) and grade 3 (2: 10.1%) NHL. Pts were eligible for entry with up to 3 prior chemotherapy (CT) and 2 immunotherapy (IT) regimens provided performance status was ≥ 1. Pts with new onset of B-symptoms, rising LDH, rapid tumor growth or greater than one year from initial diagnosis were required to undergo repeat lymph node biopsy to exclude recent transformation. Pts with CNS involvement, prior peripheral neuropathy >gr 1, HIV+, and pregnant or nursing women were also excluded. Pts were required to have Cr <2 x ULN, AST/ALT <2.5 x ULN and an ANC > 750. Median age at study entry was 60 years (36–87). Prior therapy was evaluated in 20 pts and 17/20 had received multi-agent CT while 12/20 pts received prior IT. Thalidomide was initiated at a dose of 200 mg daily and escalated by 100 mg daily every 1–2 weeks as tolerated with a maximal dose of 800 mg/d. If ≥ gr 2 peripheral neuropathy or ≥ gr 3 somnolence or mood changes occurred, the dose was held for one week and restarted at 50% of the prior daily dosage. Results: The median daily dose was 400 mg (range 50–800 mg). There was 1 complete response (CRu-residual abnormality) in a pt with SLL and one partial response in a pt with F-NHL grade 1 (ORR 8%: 95%CI: 1–26%). 16 pts had progressive disease during therapy and 2 died of disease soon after stopping therapy due to adverse events. One patient continues on therapy without progression of disease to date. The remaining 4 pts were taken off of therapy prior to the first 3 month evaluation. The reason for withdrawal was pt refusal (2) and adverse events (2). The median event free survival was 2.6 months (95% CI:1.4–4.4 mos) with a median overall survival of 23.3 months. Toxicity information on 24/25 pts revealed 4 (17%) with grade 4 neutropenia with 1/4 febrile as well. The most common grade 3 toxicities were anemia (13%), dyspnea (13%), fatigue (8%) and neurologic toxicities consisting of somnolence, dizziness, depression and anxiety (21%). Peripheral sensory neuropathy was reported as gr 2 in 8% and gr 3 in 8%. However, 38% of pts were reported as experiencing gr 2 fatigue. There were no grade 5 toxicities. Conclusion: These phase II trial results in a pretreated pt population demonstrate that, despite an acceptable toxicity profile, thalidomide has only minimal efficacy in F- NHL and SLL.

A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Andrea Borghese Apolo ◽  
Howard L. Parnes ◽  
Ravi Amrit Madan ◽  
James L. Gulley ◽  
John Joseph Wright ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Primary Objective ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Clinical Activity ◽  
Prior Therapy ◽  
Visceral Metastases ◽  
Carcinoma Of The Bladder ◽  
Grade 3

307 Background: Translational studies have shown that shed MET levels in serum and urine of pts with UC correlate with stage and visceral metastases and that cabozantinib reverses HGF-driven UC cell growth and invasion. These data support the evaluation of cabozantinib in pts with mUC. Methods: In this phase II study, pts receive cabozantinib 60 mg daily in 28-day cycles. There are 3 study cohorts (1) mUC, (2) bone only mUC (3) metastatic rare bladder histology. The primary objective is to determine the response rate (RR) by RECIST. Response is assessed every 2 cycles. Tissue, blood, and urine were collected on all pts to test for MET/HGF and immune subsets. Results: 26 out of 55 pts have enrolled (19 M, 7 F): median age 62 (42-82) and median KPS of 80%. Primary sites include bladder (77%) and upper tract UC (23%). Prior therapy includes 30% pts with 1 regimen, 39% with 2, 15% with 3, 8% with 4 and 8% with 6. 81% of pts had visceral metastases (lung, liver and bone) and 19% lymph node only metastases. 23 pts (19 in cohort 1, 3 in cohort 2 and 1 in cohort 3) were evaluable for response after completing at least 4 weeks of therapy. In cohort 1, 2 pts achieved PR (1 remained on study for 10 months and 1 remains on study after >12 months of therapy); 7 pts had SD for at least 16 weeks (1 remained on study for 11 months); 10 had PD; 1 is too early to assess for response; 1 was removed before restaging for toxicity and 1 was removed for not meeting eligibility. The objective RR is 11% and SD 37% for a clinical benefit of 48%. In cohort 2, 1 of 3 pts had a near resolution of bone lesions on NaF PET/CT for 11 months. In cohort 3, only pt enrolled (squamous cell carcinoma of the bladder) achieved SD for 16 weeks. Mixed responses with regression of lung, bone or lymph nodes were observed in 30% of pts with PD. Grade 3/4 toxicities included: fatigue (8%), hyponatremia (8%), hypophosphatemia (8%) diarrhea (4%), thromboembolism (4%), transaminitis (4%), hypothyroidism (4%), thrombocytopenia (4%), dysphonia (4%), hypomagnesemia (4%), creatinine increase (4%) and proteinuria (4%). Conclusions: Cabozantinib has clinical activity in pts with relapsed or refractory mUC with manageable toxicities. Further studies are underway to correlate response to therapy with MET expression. Clinical trial information: NCT01688999.

A phase II study of lapatinib in recurrent or metastatic EGFR and/or ErbB2 expressing adenoid cystic (ACC) and non-ACC malignant tumors of the salivary glands (MSGT)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5566-5566 ◽  
Author(s):  
M. Agulnik ◽  
E. E. Cohen ◽  
R. B. Cohen ◽  
E. X. Chen ◽  
S. J. Hotte ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Malignant Tumors ◽  
Objective Response ◽  
Therapeutic Index ◽  
Eligibility Criteria ◽  
Dual Inhibitor ◽  
Grade 3 ◽  
Present Trial

5566 Background: The limited therapeutic index of chemotherapy in recurrent or metastatic MSGT provides a strong rationale for the evaluation of molecularly targeted agents in this disease. Lapatinib is a dual inhibitor of EGFR and ErbB2 tyrosine kinase activity. Expression of ErbB2 and EGFR has been associated with biological aggressiveness and poor prognosis in MSGT, respectively. We conducted a phase II study to determine the antitumor activity of lapatinib in MSGT. Methods: The main study has a two-stage design in which patients (pts) with progressive, recurrent or metastatic ACC, and immunohistochemically expressing at least 1+ EGFR and/or 2+ ErbB2, were treated with lapatinib 1500 mg PO daily. Each cycle consists of 4 weeks of continuous dosing. Pts with non-ACC MSGT of other histologies, meeting identical eligibility criteria, were treated in this trial as a single-stage, separate cohort. Results: Of 57 pts screened for this study, 29/33 (88%) ACC and 22/24 (92%) non-ACC pts expressed EGFR and/or ErbB2. Thirty-eight pts have been accrued to the study to date (20 ACC/18 non-ACC). The remaining 13 pts who were screened positive either declined entry or were ineligible for other reasons. Baseline data on 34 pts are: M:F = 25:9, median age 56 (range 38–80), PS 0:1:2 = 16:17:1, prior radiation:chemotherapy = 30:18. After 92 cycles of therapy, the most frequent adverse events experienced (as % of cycles) were diarrhea (54%), pain (52%), fatigue (52%), lymphopenia (39%), anemia (38%), hyperglycemia (38%) and dyspnea (34%). No grade 4 adverse events have occurred and only 8 pts experienced a grade 3 adverse event, primarily pain and dyspnea. No significant cardiac toxicity has been observed. Among 14 ACC pts evaluable for response so far: 9 have SD (range 2–9 cycles), 3 PD, and 2 died prior to cycle 2. For 12 evaluable non-ACC pts: 8 have SD (range 2–9 cycles), and 4 PD. No pts have had an objective response. Conclusions: Although there are no objective responses to date, lapatinib is well tolerated, with tumor stabilization achieved by 64% of pts and 24/38 pts remain on treatment at present. Trial accrual of ACC pts into the first stage has been completed, the second stage will open if an objective response is seen. No significant financial relationships to disclose.

Final results of a phase I study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor receptors (VEGFR), in combination with carboplatin (C) + paclitaxel (T) in patients with advanced non-small cell lung cancer (NSCLC): A study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3054-3054 ◽  
Author(s):  
S. A. Laurie ◽  
A. Arnold ◽  
I. Gauthier ◽  
E. Chen ◽  
G. Goss ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Vegf Signaling ◽  
Combination Methods ◽  
Starting Dose ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Endothelial Growth Factor ◽  
Anti Tumor Activity

3054 Background: AZD2171 is a potent oral inhibitor of the tyrosine kinase activity of all VEGFR subtypes. This study was undertaken to determine the recommended phase II dose of AZD2171 in conjunction with standard doses of C and T, and to assess the tolerability, safety, PK profile and anti-tumor activity of this combination. Methods: Patients with stage IIIB / IV NSCLC (any histology); PS 0–2; no prior chemotherapy for metastatic disease and no significant hemoptysis / bleeding, were eligible. Treated, clinically stable brain metastases were permitted. C - AUC 6, and T - 200 mg/m2 over 3 hours, q3weekly. AZD2171 commenced day 2 cycle 1 at a starting dose of 30 mg po daily. PK profile of all was drugs performed during cycles 1 and 2. Response was assessed by RECIST every second cycle. Results: 20 patients were enrolled: AZD2171 30 mg (9 pts) and 45 mg (11 pts). Median age 58; 19 PS 0 / 1; 8 females. At 30 mg, one confirmed DLT was observed (grade 3 ALT); hypertension ≥ grade 2 was seen in 6 pts, prompting the institution of a standardized algorithm for management of this predictable toxicity. Of the first 3 pts enrolled to the 45 mg dose level, one DLT was observed (grade 3 febrile neutropenia with grade 3 mucositis); no further DLT was observed in the expanded cohort. Other common toxicities: fatigue, anorexia, mucositis and diarrhea. Hematologic toxicity was not greater than that expected with CT alone. No hemoptysis was seen. To date, 15 pts are evaluable for response: 6 PR, 8 SD and 1 PD. Many SD pts had evidence of tumor shrinkage, including central cavitation. Conclusions: Toxicities of this combination appear manageable and predictable. Full single-agent dose of AZD2171 may be administered with standard C+T. Hypertension, a typical toxicity of inhibitors of VEGF signaling, was observed but manageable. Encouraging anti-tumor activity of the combination has been observed. NCIC CTG BR.24, a phase II/III trial of C+T with AZD2171/placebo is underway. [Table: see text]

An interim analysis of a phase II study of the combination of TACE and sorafenib in patients with unresectable hepatocellular carcinoma in National Cancer Center Korea (COTSUN KOREA, NCT00919009).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 253-253 ◽  
Author(s):  
J. Park ◽  
H. Kim ◽  
J. Shim ◽  
S. Woo ◽  
J. Choi ◽  
...  
Keyword(s):  
Adverse Events ◽  
Skin Reaction ◽  
Phase Ii ◽  
Interim Analysis ◽  
Preliminary Evidence ◽  
Cancer Center ◽  
Close Monitoring ◽  
Pugh Class ◽  
Grade 3 ◽  
Vegfr Inhibitor

253 Background: Transarterial chemoembolization (TACE) is the palliative treatment for patients with unresectable HCC. TACE-induced ischemic injury is known to increase circulating VEGF and related with poor prognosis.The aim of this study is to evaluate efficacy and safety of combined TACE with sorafenib, VEGFR inhibitor in unresectable HCC patients. Methods: This study is a non-randomized, open-labeld, single-arm, phase II investigator-initiated clinical study. Estimated number of subjects was 50 under the assumption of 3.2 months of median time to progression (TTP) with TACE alone. All patients are Child-Pugh class A or superb B. Sorafenib begins to be administered on 3 days after the first session of TACE and will be subsequently administered up to 24 weeks. Efficacy of TACE was evaluated after 4 weeks from TACE by dynamic CT. Repeated TACE is performed “on demand” in case of PR or SD according to CT/MRI evaluation. Results: A total of 50 patients were enrolled for this interim analysis. Male was 84% and mean age was 61.5years. Causes of underlying chronic liver disease were HBV in 28 patients (65.1%). Patients were categorized into modified UICC stage II (15, 30.0%), III (24, 48.0%) and IVA (11, 22.0%). Median follow-up period was 5.3 months (range, 1.0–13.1). The size of index lesions was ranged from 1.0 cm to 13.1 cm, and number of lesions was between 1 and 5. Number of TACE sessions was 1.0 (range, 1–4). Common adverse events (AE) during sorafenib therapy were elevation of serum AST/ALT (96.8%), hypocalcemia (90.0%), thrombocytopenia (84.0%), and hyperbilirubinemia (76.0%). Hand-foot skin reaction was most frequently observed among AE of NCI CTCAE grade 3 or higher (40.0%), followed by elevation of serum ALT (38.0%). Dose reduction of sorafenib was needed most commonly due to hand-food skin reaction (n=29). Median TTP was 5.1 months (range, 3.8–6.3). Conclusions: Adverse events were approved as acceptable by independent monitoring system. Preliminary evidence of antitumor activity was also observed. This trial can be safely performed with close monitoring in inoperable and/or unresectable HCC patients. No significant financial relationships to disclose.

A phase II study of dasatanib (BMS 354825) in recurrent or metastatic ckit-expressing adenoid cystic (ACC) and non-ACC malignant salivary glands tumors (MSGT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6022-6022
Author(s):  
Stuart J. Wong ◽  
Ezra E.W. Cohen ◽  
Theodore Karrison ◽  
David N. Hayes ◽  
Merrill S. Kies ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Study Drug ◽  
Protein Product ◽  
Stage I ◽  
Stage Ii ◽  
Best Response ◽  
Grade 3

6022 Background: ACC is a rare disease, accounting for 1/3rd of MSGT, in which 90% of cases express the protein product of the ckit proto-oncogene. Dasatinib is a potent and selective inhibitor of five oncogenic PTKs/kinase families including ckit. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. Methods: In a two-stage design, adult patients (pts) with recent radiographic progressive, recurrent or metastatic ACC, + cKIT, were treated with dasatinib 70 mg PO BID. Pts with non-ACC MSGT of other histologic types, were treated as a separate cohort. Response was assessed every 8 wks by imaging using RECIST criteria. The study design stipulated enrollment of n=40 ACC patients (20 in stage I and 20 in stage II) and 25 non-ACC patients (14 in stage I and 11 in stage II). Results: Fifty-four pts were enrolled, 40 ACC and 14 non-ACC. One additional pt was a screen failure. Baseline data on 54 pts are: M:F = 28:26, median age 56.6 yrs (range 20-82), PS 0:1:2 = 24:28:2, prior radiation:chemotherapy = 44:21. The most frequent adverse events experienced (as % of pts, worst grade 2 or higher and at least possibly related to study drug) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (11%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), and non-cardiac chest pain (6%). No grade 4 adverse events occurred and only 15 pts experienced a grade 3 adverse event (at least possibly attributed to study drug), primarily dyspnea (4 patients) and fatigue (3 patients). Significant cardiac toxicity was observed in one pt (grade 3 prolonged QT corrected interval). Among ACC pts, best response to dasatinib: 0 pts (0%) had PR, 21 pts (52%) had SD (range 2.8-13.8 months), 12 pts (30%) had PD, and 2 died prior to cycle 2. Median PFS was 4.8 mos. For 14 evaluable non-ACC pts, none had an objective response, triggering early stopping. 7 had SD (range 1.4-6.6 months), and 4 PD. Conclusions: Although there were no objective responses, dasatinib is well tolerated, with tumor stabilization achieved by 52% of ACC pts. Dasatinib demonstrated no activity in non-ACC MSGT. Clinical trial information: NCT00859937.

Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study

2008 ◽  
Vol 26 (14) ◽  
pp. 2320-2326 ◽  
Author(s):  
Peter S. Kozuch ◽  
Caio Max Rocha-Lima ◽  
Tomislav Dragovich ◽  
Howard Hochster ◽  
Bert H. O'Neil ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Sensory Neuropathy ◽  
Primary Objective ◽  
Response To Treatment ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

PurposeTo evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC).Patients and MethodsPatients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2(arm A) or bortezomib 1.3 mg/m2plus irinotecan 125 mg/m2(arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability.ResultsA preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade ≥ 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B.ConclusionBortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.

Immune checkpoint inhibitor induced hepatitis: Risk factors, outcomes, and impact on survival.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14525-e14525
Author(s):  
Abdul Miah ◽  
Songzhu Zhao ◽  
Sandip H. Patel ◽  
Andrew Johns ◽  
Madison Grogan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Comprehensive Cancer Center ◽  
Rank Test ◽  
Cancer Center ◽  
Grade 3

e14525 Background: Immune checkpoint inhibitors (ICIs) have improved the survival of patients with multiple cancer types, however ICI treatment is associated with a unique set of immune-related adverse events (irAEs) that can affect any organ. Few studies have evaluated the risk factors and outcomes of ICI induced hepatitis (ICIH). Methods: We utilized an institutional database of patients with advanced cancers treated with ICI between 2011 and 2017 at The OSU Comprehensive Cancer Center to identify patients with ICIH. Any patient who received at least one dose of ICI alone or in combination with other systemic therapies either as part of clinical trial or standard of care were included. Clinical data were extracted through chart abstraction. irAEs were graded using the Common Terminology Criteria for Adverse Events v5. Overall survival (OS) was calculated from the date of ICI initiation to death from any cause or the date of the last follow-up. OS with 95% confidence intervals were estimated using the Kaplan–Meier method. OS was also evaluated by occurrence of ICIH using the log-rank test. Results: We identified 1,096 patients treated with at least one dose of ICI. Most common cancers included lung (n=224, 20%) and melanoma (n=342, 31%). The most common ICIs were PD1/L1 (n=774, 71%) and CTLA-4 inhibitors (n=195, 18%). ICIH of any grade occurred in 64 (6%) patients. Overall, 46 (71%) were male and median age was 60 years. Severity of hepatitis was grade 1-2 in 30 patients (47%) (Table 1). The incidence of ≥grade 3 ICIH in the entire cohort was 3.1%. Median time to ICIH diagnosis was 63 days. ICIH occurred alone in 24 patients, and co-occurred with other irAEs in 40 patients. The most common co-occurring irAEs were pneumonitis (n=7); colitis (n=15), thyroid abnormality (n=14); and dermatitis (n=15). ICIH was more common in women (p=0.038), in patients treated with combination ICIs (p<0.001), and among patients receiving first line therapy (p=0.018). Patients who developed ICIH had significantly longer OS than patients who did not develop ICIH; there was no difference in OS between patients with ≥grade 3 ICIH vs grade 1-2 (Table). 33 out of 34 patients with ≥grade3 ICIH were treated with steroids; 3 received mycophenolate and one received infliximab. Of patients with ≥grade 3 ICIH, 11 resumed ICI therapy without recurrent ICIH. Conclusions: Female sex, combination immunotherapy, and line of therapy were associated with ICIH. Patients with ICIH had improved clinical outcomes compared to those that did not develop ICIH, even those with higher grade toxicity. Further study is needed to assist in developing risk stratification models and optimal treatment for ICIH. OS of patients with and without immune checkpoint inhibitor hepatitis.[Table: see text]

Phase II Study of Lenalidomide (CC-5013, Revlimid®) for Patients (pts) with Myelofibrosis (MF).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 377-377
Author(s):  
Jorge Cortes ◽  
Deborah Thomas ◽  
Srdan Verstovsek ◽  
Francis Giles ◽  
Miloslav Beran ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Myeloproliferative Disorders ◽  
Clinical Activity ◽  
Toxicity Profile ◽  
Prolonged Administration ◽  
Prior Therapy ◽  
Days Of Therapy ◽  
Grade 3 ◽  
Baseline Hemoglobin

Abstract Introduction: Thalidomide has been shown to induce responses in pts with MF but prolonged administration in these pts may be associated with neurotoxicity and other adverse events. Lenalidomide is the lead clinical compound in a new group of drugs called IMiDs®, which have immunomodulatory properties. It affects cytokine expression 200–5000 times more potently than thalidomide but lacks the teratogenecity, sedation and neurotoxicity. Methods: We thus designed a phase II study for pts with myelofibrosis (primary or associated with myeloproliferative disorders) with a platelet (plt) count of at least 30 x109/L. Pts may have received prior therapies, but were excluded if they had known hypersensitivity to thalidomide. Pts received lenalidomide 10 mg/day orally (5 mg daily for patients with platelet count less than 100,000 at study entry). Results: We have treated 41 pts. Their median age was 65 (range, 42 to 83). Thirty-six pts (88%) had received prior therapy for MF, including thalidomide 13 (32%), hydroxyurea 12 (29%), interferon 11 (27%) (pegylated 7), anagrelide 10 (24%), and erythropoietin 6 (15%). Baseline hemoglobin was &lt;10g/dl in 19 (46%) (13, 32% transfusion dependent); platelets &lt;100 x109/L in 12 (29%); neutrophils &lt;1.5 x109/L in 2 (5%), and 20/34 (59%) had splenomegaly (median 10cm BCM, range 1 to 30) (7 prior splenectomy). Twenty pts are evaluable for response and toxicity (i.e., received at least 30 days of therapy, unless discontinued because of progression or toxicity). One pt discontinued therapy because of toxicity (grade 3 rash). Responses have been observed in 10 (50%) pts. These include CR in 2 pts (normalization of Hgb and WBC, respectively), PR in 2 pts (improvement in plts and hgb, ± spleen), hematologic improvement in 6 pts (improvement in plts 3, spleen 2, WBC 1). Three of 13 transfusion-dependent pts have become transfusion independent. The median time to response was 9 weeks (range, 2 to 22). Responses have been sustained for a median of 14 weeks (range, 2 to 28 weeks). Therapy has been well tolerated. The more common toxicities were rash in 12 (29%), and pruritus in 8 (20%). Grade ≥ 3 toxicities were thrombocytopenia (n=2), rash (n=1), fatigue (n=1), and neutropenia (n=1). Four (10%) pts have required dose reduction and 1 discontinued therapy because of toxicity (rash). Conclusion: We conclude that lenalidomide has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile. Studies using lenalidomide in combination with other agents are justified.

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