Pharmacology and safety factors affecting use of flat (rather than weight-based) dosing of tesetaxel, an orally administered taxane

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2510-2510
Author(s):  
R. P. Warrell ◽  
M. Beeram ◽  
E. Spindler ◽  
K. Papadopoulos ◽  
A. Patnaik ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Maximum Tolerated Dose ◽  
Repeat Dose ◽  
Breast Cancers ◽  
Phase 2 ◽  
Clinical Safety ◽  
Factors Affecting ◽  
Future Studies ◽  
Starting Dose ◽  
Grade 3

2510 Background: As a class, taxanes have wide interpatient (pt) pharmacokinetic (PK) variability at their effective dose, which has been associated with adverse reactions, especially neutropenia. Tesetaxel is an oral taxane with Phase 2 activity in pretreated pts with colorectal, non-small cell lung, gastric, and breast cancers. Tesetaxel is not a substrate for P-glycoprotein; it is associated with lower neurotoxicity at equi-myelotoxic does, and it displays a long terminal half-life in plasma (∼180 hrs). We explored PK and clinical safety to determine the feasibility of using flat dosing in future studies. Methods: PK parameters were evaluated in 21 pts treated at the maximum tolerated dose (27 mg/m2) either alone or in combination with capecitabine. We then compared actual dose (total mg) with the weight-based dose and correlated the incidence and severity of Grade 3–4 neutropenia with weight-based vs. flat dosing. Results: A total of 174 pts were treated with tesetaxel in Phase 2 trials at doses of 27 or 35 mg/m2 once every 3 weeks. For pts prescribed with weight-based dosing (27 mg/m2), mean Cmax in 3 separate cohorts was 24.6, 42.5, and 47.9 μg/L, with AUC0-inf of 1363, 1592, and 1663 h*μg/L, respectively. In 103 pts prescribed a dose of 27 mg/m2, 17% and 16% of pts received doses of 40 mg or 60 mg, respectively, whereas 67% received 50 mg. Correlations between drug exposure AUC0-inf and actual dose (mg and mg/m2) across the entire range of administered doses showed r2 values of 0.455 and 0.492, respectively. Similar correlations after a second repeat dose showed r2 values of 0.731 and 0.653, respectively. The incidence of Grade 3–4 neutropenia at 27 mg/m2 was 33%. Conclusions: PK and clinical safety suggest that weight-based dosing offers no substantial advantage compared with flat dosing. Future studies could incorporate a starting dose of 50 mg administered once every 3 weeks. Flat dosing should also be tested using different schedules, including weekly x 3 weeks and “metronomic dosing” (1–2 mg/d). [Table: see text]

scholarly journals Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Blood ◽  
2019 ◽  
Vol 133 (18) ◽  
pp. 1964-1976 ◽  
Author(s):  
Andrew D. Zelenetz ◽  
Gilles Salles ◽  
Kylie D. Mason ◽  
Carla Casulo ◽  
Steven Le Gouill ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Phase 2 ◽  
Non Hodgkin Lymphoma ◽  
Phase 1B ◽  
Grade 3

Abstract Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1625-1625
Author(s):  
Keita Kirito ◽  
Norio Komatsu ◽  
Kazuya Shimoda ◽  
Hikaru Okada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Spleen Size ◽  
Phase 2 ◽  
Spleen Volume ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Starting Dose ◽  
Grade 3 ◽  
Eortc Qlq

Abstract BACKGROUND: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly and MF-related symptoms, and has been associated with improved overall survival in patients (pts) with MF in randomized clinical trials. Results from the phase 2 Asian multinational study (NCT01392443) supported these findings in Asian pts, including 30 Japanese pts. The current study was initiated to collect further data on the safety and efficacy of ruxolitinib in pts with MF and included intermediate (Int)-1-risk pts and those with a platelet (PLT) count of 50 to < 100 × 109/L, 2 pt populations not included in the phase 3 COMFORT studies or the phase 2 Asian study. METHODS: Pts with primary MF (PMF), post-polycythemia vera (PPV) MF, or post-essential thrombocythemia (PET) MF classified as high-risk, Int-2 risk, or Int-1 risk with a palpable spleen (≥ 5 cm from costal margin) were included. The primary objective was to assess safety of ruxolitinib. Efficacy endpoints included changes in spleen size and patient-reported outcomes (EORTC QLQ-C30 symptoms and functional scales and the 7-day modified MFSAF v2.0). All pts were to receive ruxolitinib for 24 wk with the starting dose based on PLT count at baseline (50 to ˂ 100 × 109/L, 5 mg twice daily [bid]; 100 to 200 × 109/L, 15 mg bid; ˃ 200 × 109/L, 20 mg bid) and adjusted for each pt to maximize safety and efficacy (minimum, 5 mg bid; maximum, 25 mg bid). The primary analysis occurred when all pts completed 24 wk or discontinued. RESULTS: Overall, 51 pts (PMF, n = 23; PPV-MF, n = 14; PET-MF, n = 14) were treated. Most pts were Int-2 (33.3%) or high risk (54.9%); 11.8% were classified as Int-1. The median age was 65 years (range, 44-85 years), and 52.9% (n = 27) were male. The median palpable spleen length was 16.5 cm (range, 2-30 cm), and the median spleen volume was 2028.7 cm3 (range, 480-4682 cm3). Median hemoglobin at baseline was 99.0 g/L (range, 62-141 g/L), and median PLT count was 247 × 109/L (range, 57-1265 × 109/L); 13.7% of pts had a baseline PLT count of 50 to < 100 × 109/L. Most pts received a starting dose of 20 mg bid (62.7%; n = 32) or 15 mg bid (23.5%; n = 12); the rest started treatment at 5 mg bid. Most pts completed treatment as per protocol (86.3%; n = 44); 9.8% (n = 5) discontinued due to adverse events (AEs). Other reasons for discontinuation included disease progression and loss to follow-up (2.0% each). The most common hematologic AEs were anemia (62.7%; grade 3/4, 47.1%) and thrombocytopenia (29.4%; grade 3/4, 7.8%). Nonhematologic AEs in ≥ 10% of pts included constipation (13.7%; grade 3/4, 0%), abnormal hepatic function (11.8%; grade 3/4, 3.9%), and nasopharyngitis (11.8%; grade 3/4, 0%). No deaths occurred on study. At wk 24, 30.0% of evaluable pts (15/50) experienced ≥ 50% reduction in palpable spleen length from baseline; 26.0% (13/50) had a ≥ 35% reduction in spleen volume. The majority of pts (52.0%; 26/50) had a ≥ 50% reduction in palpable spleen length from baseline at any time by wk 24; 38.0% (19/50) had a ≥ 35% reduction in spleen volume by wk 24. Ruxolitinib treatment led to clinically significant improvements in symptoms, with 75.0% of evaluable pts (30/40) achieving a ≥ 50% reduction from baseline in MFSAF total symptom score at wk 24. Improvements were also observed in quality of life and role functioning (as assessed by the EORTC-QLQ), with pts reporting reductions in MF-related symptoms, including fatigue, pain, and appetite loss. Overall, IgM, CD3, CD4, and CD8 levels remained stable during treatment; IgG levels decreased slightly in the first 4 wk but then increased to near baseline levels (Figure). CONCLUSIONS: As observed in other studies of ruxolitinib, most pts in this study experienced spleen size reductions and improvement in symptoms. The most common AEs were anemia and thrombocytopenia, consistent with previous reports. Additionally, this study evaluated the effect of ruxolitinib on the levels of different immune markers, an analysis not conducted in previous studies with ruxolitinib, and identified no negative effects on the levels of these markers during the course of treatment. The safety and efficacy of ruxolitinib here is consistent with the phase 3 COMFORT studies and the phase 2 Asian study. These findings indicate that ruxolitinib is a safe and effective therapy in Japanese pts with MF, including Int-1-risk pts and those with PLT counts 50 to < 100 × 109/L. Disclosures Kirito: Novartis Pharma KK: Honoraria. Shimoda:Novartis: Consultancy, Honoraria. Okada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Yonezu:Novartis Pharma K.K.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

Phase I study of BAY 73–4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3593-3593 ◽  
Author(s):  
S. Hedbom ◽  
S. Steinbild ◽  
A. Frost ◽  
M. Büchert ◽  
C. Unger ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Exposure Level ◽  
Phase Ii Trials ◽  
Multikinase Inhibitor ◽  
Dce Mri ◽  
Grade 3

3593 Background: BAY 73–4506 is a multikinase inhibitor targeting both the tumor and its vasculature. BAY 73–4506 inhibits VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf). This drug shows potent, oral activity in a wide variety of preclinical xenograft models. Methods: This phase I dose-escalation trial investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers included dynamic contrast-enhanced MRI (DCE-MRI) and circulating sVEGFR-2 and VEGF levels assessed at each cycle. Tumor response was evaluated per RECIST criteria. Results: 22 patients (pts) with documented progressive disease were enrolled at doses of 10 mg to 120 mg once daily. Tumor types included CRC (27%), RCC (18%) and pancreatic cancer (14%). Pts had received a median of 3 prior therapies, including anti-VEGF agents in 5 pts. BAY 73–4506 PK appeared linear with dose; the AUC target exposure level of 13 mg*h/L (from preclinical models) was reached at 30 mg. The major metabolite of BAY 73–4506 (active in vitro) reached a similar AUC(0–24)ss as the parent drug at 120 mg. Commonly reported drug-related adverse events (=10% of pts) were hoarseness (7 [32%], all CTC grade 1), hypertension (5 [23%], all CTC grade 1–2), fatigue (3 [14%], CTC grade 3 in 1 pt [5%]), hand-foot-skin reaction (HFSR) (3 [14%], CTC grade 3 in 1 pt [5%], mucositis (3 [14%], all CTC grade 1). Maximum tolerated dose was exceeded at 120 mg with dose-limiting toxicities including fever without documented infection, HFSR, fatigue, and leukopenia. 2 pts (RCC & osteosarcoma) achieved RECIST partial response. 4 pts had stable disease, one of them a cervical cancer pt with extensive tumor cavitation. PD parameters (decrease in sVEGFR-2 levels, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure. Conclusions: BAY 73–4506 was well tolerated at 60 mg with report of dose-limiting toxicities at 120 mg. 6 (28%) of 22 pts demonstrated antitumor activity. Optimal dose and regimen are under evaluation in preparation for phase II trials. No significant financial relationships to disclose.

Phase I study of vandetanib (ZD6474) administered during and after irradiation (RT) in children with diffuse intrinsic pontine glioma (DIPG)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10020-10020
Author(s):  
A. Broniscer ◽  
T. E. Merchant ◽  
C. Hillenbrand ◽  
Z. Patay ◽  
T. K. Chin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Drug Exposure ◽  
Dosage Level ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pharmacokinetic Analysis ◽  
Dismal Prognosis ◽  
Grade 3

10020 Background: Children with DIPG have a dismal prognosis despite use of RT, which is the mainstay of therapy. All chemotherapy regimens used so far demonstrated no benefit. EGFR and VEGFR pathways are considered important in tumorigenesis of DIPG. Methods: We conducted a traditional phase I study combining oral vandetanib (VEGFR-2 and EGFR inhibitor) during and after local RT in children with DIPG. Five dosage levels were tested (50, 65, 85, 110, and 145mg/m2 per day). Vandetanib and RT started on the same day. The first 6 weeks of therapy constituted the dose-limiting toxicity (DLT)-evaluation period. Correlative studies consisted of pharmacokinetic analysis (PK), pharmacodynamic studies in blood, and standard and investigational imaging (before and 1, 3, and 6 weeks after start of therapy). Results: Twenty-one patients were enrolled on study (50 [n = 3], 65 [n = 3], 85 [n = 3], 110 [n = 6], and 145mg/m2 [n = 6]). Two patients experienced DLT consisting of rash/mucositis (level 4) and diarrhea (level 5). The maximum-tolerated dose (MTD) of vandetanib was not reached. Other significant toxicities included lymphopenia grade 3/4 (n = 10), grade 3 neutropenia and hypophosphatemia (one each), grade 2 proteinuria (n = 2), grade 2 hypertension (n = 4), and mild QTc prolongation (n = 7) .Once the phase I component was completed, two extra patients were enrolled at dosage level 5; one of them developed grade 4 seizure secondary to posterior reversible encephalopathy syndrome. PK (n = 21) showed similar drug clearance and volume of distribution compared to adults. However, drug exposure at steady state normalized by dose seemed higher in children. Increased tumor perfusion during the first 6 weeks of therapy was observed in the first 12 patients analyzed. Conclusions: Although MTD was not reached, we recommend administration of vandetanib at a dose of 110mg/m2 per day during and after local RT in children. Further combination studies of vandetanib in children with DIPG are planned. No significant financial relationships to disclose.

A phase I study of mesothelin-targeted immunotoxin LMB-100 in combination with nab-paclitaxel for patients with previously treated advanced pancreatic cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 307-307 ◽  
Author(s):  
Christine Campo Alewine ◽  
Raffit Hassan ◽  
M. Iqra Ahmad ◽  
Jane B Trepel ◽  
Cody Peer ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Exposure ◽  
Bowel Perforation ◽  
Advanced Pancreatic Cancer ◽  
Elongation Factor ◽  
Maximum Tolerated Dose ◽  
Pseudomonas Exotoxin A ◽  
Previously Treated ◽  
Grade 3 ◽  
Anti Tumor Activity

307 Background: LMB-100 is a Pseudomonas exotoxin A-based immunotoxin that targets mesothelin (MSLN). MSLN is expressed by >75% of pancreatic adenocarcinomas (PDAC). LMB-100 kills MSLN-expressing cells by irreversibly modifying elongation factor-2 to halt protein synthesis. Phase I studies of LMB-100 defined the maximum tolerated dose (MTD) of 140 mcg/kg IV given on D1, 3 and 5 of a 21-day cycle. Development of anti-drug antibodies (ADAs) limited patient drug exposure beyond cycle 2. Our pre-clinical data showed that combination of LMB-100 with a taxane resulted in synergistic anti-tumor activity. Methods: We conducted a phase I single center study (standard 3+3 design) to determine the MTD of LMB-100 given with nab-paclitaxel in patients with previously treated advanced PDAC. LMB-100 was given on D1, 3 and 5 of a 21-day cycle, and nab-paclitaxel (125 mg/m2) on D1 and D8. Initial patients could receive a maximum of 4 cycles, but subsequently a 2-cycle maximum was employed. Results: Fourteen patients (median age 58) were enrolled. Two of 6 patients experienced DLTs at the 100 mcg/kg dose of LMB-100 (myalgia- 2 pts, fatigue- 1 pt, hypotension- 1 pt; all grade 3). One of 8 patients had DLT at the 65 mcg/kg dose (edema, urine output decrease- both grade 3). Other toxicities related to LMB-100 included hypoalbuminemia, edema-associated weight gain, hyponatremia, fatigue, drug fever, infusion-related reaction, hypophosphatemia, nausea and anorexia. One patient died on treatment from complications of bowel perforation attributed to cancer. All patients achieved detectable serum levels of LMB-100 during the first cycle, even those with pre-existing ADAs, and 5 of 8 did so during cycle 2. One patient receiving the 65 mcg/kg dose had a confirmed partial response, and CA 19-9 dropped by > 50% in 5 of 8 evaluable patients. Conclusions: MTD of LMB-100 is 65 mcg/kg given with nab-paclitaxel on this schedule. Anti-tumor activity was observed. A phase II cohort is currently being accrued. Clinical trial information: NCT02810418.

Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10012-10012 ◽  
Author(s):  
B. C. Widemann ◽  
E. Fox ◽  
P. C. Adamson ◽  
S. Baruchel ◽  
A. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Eligibility Criteria ◽  
Starting Dose ◽  
Hand Foot Syndrome ◽  
Normal Alt ◽  
Grade 3 ◽  
Dose Levels

10012 Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m2/dose dose levels. Results: 34 eligible pts [16M, median age 14.6 yrs, (range, 5–21)] with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m2) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m2, and the dose was re-escalated to 150 mg/m2 with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m2 and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m2. At 200 mg/m2 only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC0–24h was similar at 150 mg/m2 (28±24 μg · h/mL, n = 9) and 200 mg/m2 (28±17 μg · h/mL, n = 4). Tmax was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p < 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m2, similar to the adult recommended dose (400 mg). No significant financial relationships to disclose.

Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 278-278 ◽  
Author(s):  
Eileen Mary O'Reilly ◽  
Lon S. Smith ◽  
Johanna C. Bendell ◽  
John H. Strickler ◽  
Mark Zalupski ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Regression ◽  
Single Agent ◽  
Notch Pathway ◽  
Maximum Tolerated Dose ◽  
Hair Follicles ◽  
Stem Cell Markers ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Grade 3

278 Background: Tarextumab (TRXT), fully human IgG2 antibody, inhibits signaling Notch 2, 3 receptors. Tumor regression seen in Notch 3 patient-derived PC xenografts when TRXT added to Nab-P+Gem. The maximum tolerated dose (MTD) of single agent TRXT was 7.5mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was Grade 3 diarrhea. This study evaluates MTD, pharmacokinetics (PK), pharmacodynamics (PD) and early efficacy of TRXT + Nab-P+Gem in mPC. Methods: Cohorts of 3-6 pts treated at 6 dose levels of TRXT. TRXT IV Days 1 + 15 with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1000mg/m2on Days 1, 8, 15 of every 28-day cycle. Biomarker analysis of surrogate tissue and tumor undertaken. Results: By 08/22/14, N= 40 treated. TRXT 15 mg/kg selected as Phase 2 dose. 1 DLT Grade 3 diarrhea in 15 mg/kg cohort. Frequently reported (≥15%) TRXT adverse events(AEs) were: diarrhea(60%), fatigue(43%), anemia(28%), decreased appetite (18%) and nausea(15%); most grade 1 or 2 and managed supportively. Other AEs (≥ 30%) were: cytopenia, alopecia, vomitng and peripheral edema. GEM or Nab-P+Gem did not alter PK of TRXT. Notch pathway-related genes, HEYL, HES2, NOTCH2 and cancer stem cell markers were altered in hair follicles at TRXT > 7.5 mg/kg combined with Nab-P+Gem. Plasma, blood RNA biomarkers were also modulated by TRXT + Nab-P+Gem. Conclusions: TRXT + Nab-P+ Gem is well tolerated. 15 mg/kg is the selected Phase 2 dose of TRXT. Encouraging anti-tumor activity was observed. Final safety, efficacy, PK and PD results in surrogate and serial tumor tissues will be presented. The Phase 2 randomized, placebo-controlled ALPINE study is underway. Clinical trial information: NCT01647828. [Table: see text]

Final Clinical Results of a Phase 2 NCI Multicenter Study of Romidepsin in Recurrent Cutaneous T-Cell Lymphoma (Molecular Analyses Included).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1568-1568 ◽  
Author(s):  
Susan Bates ◽  
Richard Piekarz ◽  
John Wright ◽  
Robin Frye ◽  
William Douglas Figg ◽  
...  
Keyword(s):  
T Cell ◽  
Multicenter Study ◽  
Drug Exposure ◽  
Cell Lymphoma ◽  
Clinical Results ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 2 ◽  
Molecular Analyses ◽  
Grade 3

Abstract Background: Responses to the novel HDAC inhibitor romidepsin were observed in patients (pts) with T-cell lymphoma in a phase 1 NCI trial. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced cutaneous T-cell lymphoma (CTCL). As an exploratory endpoint, to examine the molecular effects of romidepsin in both CTCL and peripheral T-cell lymphoma (PTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 71 CTCL pts from the NCI and 9 extramural sites. PTCL pts were also enrolled. Clinical results for pts with CTCL and biomarker analyses for both PTCL and CTCL are presented here; clinical results for the PTCL pts are presented elsewhere. This study is now closed to accrual. Pts with recurrent CTCL (Stages IA-IVB) received romidepsin at 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 q 28 days. Responses were assessed using a composite endpoint that evaluated overall changes in skin (modified Physicians Global Assessment), lymph nodes, extranodal visceral lesions and abnormal circulating T-cells. Molecular endpoints evaluated in NCI pts were: histone acetylation in peripheral blood mononuclear cells (PBMCs); MDR-1 gene expression in PBMCs and in biopsy samples; and blood fetal hemoglobin levels. Results: 71 pts (48 men and 23 women) with a mean age of 56 yrs (range 28–84) were enrolled and received romidepsin; 63 pts received ≥2 cycles of therapy. Mean number of prior therapies was 3.4 (range 1–10). Objective disease response rates (ORR) are presented in the table. Overall disease control (CR+PR+SD90) was 62% in all pts and 70% in pts who received ≥2 cycles. Target skin lesions were followed and changes were generally similar to overall skin changes. Median duration of response (DOR) was 11 months (mo) and the maximum DOR as of data cut-off was 5.5+ yrs. The most frequent drug-related AEs (all grades, all cycles) were generally mild, including nausea (82%; 4% ≥grade 3), fatigue (73%; 14% ≥ grade 3), electrocardiogram T-wave amplitude decreased (69%, 0% ≥grade 3); hemoglobin decreased (59%, 9% ≥grade 3), and platelet count decreased (59%; 13% ≥grade 3). Six pts died within 30 days of study drug administration: 2 after salvage chemotherapy, 1 with ARDS due to PD, 2 with infection, and 1 of unknown cause; 2 of these deaths were considered possibly related to treatment. An increase in all biomarkers measured was observed, although not in all pts. Correlation between global histone H3 acetylation (AcH3) at the 24-hr time point and Cmax, AUC, and clearance was observed (r = 0.37, 0.36, and −0.44, respectively, p = 0.03). Pts with major responses were more likely to have higher levels of AcH3 at 24 hr. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 35% and median DOR of 11 mo in all pts) of romidepsin in pts with recurrent CTCL. Significant responses were observed at all stages of disease, including an ORR of 32% in all pts with stage ≥IIB and 20% in all pts with stage IV. Time to response was rapid, within 2 mo in most pts, and responses were durable, &gt;6 mo in most pts. Molecular analyses confirmed that romidepsin inhibits its target deacetylases in pts. Increases were not observed in all pts, perhaps reflecting, in part, variable drug exposure or variable response to HDAC inhibition. Correlation of global acetylation with PK parameters suggests that increased drug exposure results in increased global acetylation. All Pts N=71 Pts ≥ 2 cycles N=63 ORR (CR+PR), n (%) 25 (35%) 25 (40%) PR, n (%) 21 (30%) 21 (33%) CR, n (%) 4 (6%) 4 (6%) SD90, n(%) 19 (27%) 19 (30%) Overall disease control (CR+PR+ SD90) 44 (62%) 44 (70%) DOR 11 (1+ mo, 5.5+ yrs) 11 (1+ mo, 5.5+ yrs) OR for pts with stage ≥ IIB, n (%) 20/62 (32%) 20/55 (36%) SD90= stable disease for ≥90 days

An Open-Label Phase 2 Study of Lenalidomide in Combination with Oral Dexamethasone in the Previously Untreated, Symptomatic Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2895-2895 ◽  
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Luisa Del Rizzo ◽  
Lisa W Le ◽  
Ellen Nong Wei ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Abstract 2895 Introduction: Lenalidomide is an immunomodulatory agent with promising anti-tumor activity in CLL. The use of lenalidomide in this disease, however, can be complicated by tumor lysis syndrome (TLS) and frequent tumor flare (TF). From our experience using low-dose lenalidomide (starting dose 2.5mg, titrating to a target of 10mg daily), TLS can be prevented but TF remains frequent (Chen et al. JCO 2010). In addition, when using low-dose single-agent lenalidomide, few complete responses (CR) are achieved. We therefore proposed the combination of lenalidomide and pulse dexamethasone, aiming to enhance anti-tumor activity through both synergy and mitigation of toxicities such as TF, enabling escalation to higher doses of lenalidomide. Our previous observation of “rebound” peripheral lymphocytosis when using intermittent dosing of lenalidomide led to the current use of continuous daily dosing. We present an interim analysis of the initial 18 of 31 planned pts in this ongoing trial of lenalidomide and dexamethasone as first-line CLL therapy. Methods: Eligible pts were previously untreated with symptomatic CLL (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The starting dose for lenalidomide is 5mg daily continuously, with 5mg escalations every 28 days to a maximum of 25 mg, and dexamethasone 12 mg daily orally days 1–7, 14, 21 of each 28 day cycle, both to a maximum of 18 cycles. Supportive measures: allopurinol for TLS prophylaxis, DVT prophylaxis with low dose ASA, sulfatrim for PJP prophyaxis. Results: Demographics: To date, 18 pts have been enrolled: median age 61 yrs (range 40–84), male 13 pts (72%), Rai stage III-IV 13 pts (72%), baseline median Hb 98g/L (range 77–137), absolute lymphocytes 194.5 ×109/L (range 9.3–469.9), ß2M 319 nmol/L (range 253–813; normal <170), bulky nodes 15 pts (83%), organomegaly 9 pts (50%), del17p/del11q on FISH 3 pts (17%), ZAP70+ 12 pts (67%) and unmutated IgVH in 9 of 17 pts tested (53%). Seventeen pts have received at least 1 cycle and are evaluable for toxicity and response. The median number of cycles received is 8 (range 1–18). Hematologic toxicity: 9 pts (53%) have developed Gr 3–4 neutropenia during at least 1 cycle; 4 pts (24%) febrile neutropenia; 6 pts (35%) have required GCSF support. Only 2 pts (12%) have developed Gr 3–4 thrombocytopenia, without bleeding. Nonhematologic toxicity: Non-desquamating rash (65%), fatigue (59%), diarrhea (53%), cough (53%), insomnia (47%), and constipation (47%), are common (most grade 1–2). Grade 3–4 toxicities include: atrial fibrillation with pulmonary embolism (1 pt), fatigue (2 pts), insomnia (1 pt), skin rash (1 pt), diarrhea (1 pt), muscle weakness (1 pt), infection (1 pt). Infections are frequent (all grades in 50% of pts, grade 3 in 6%), primarily affecting upper airway/lungs. One pt developed H1N1 influenzae, complicated by aspergillus pneumonia and multiorgan failure. In contrast to the high rate of TF from our previous single-agent lenalidomide trial (88%), TF is considerably less common in the current trial (5 pts; 29%). No TLS has been noted. Dose modifications/study withdrawals: The maximum 25mg dose has been achieved in 4 pts, with a median tolerated daily dose of 15 mg (range 2.5–25 mg). Grade 3–4 neutropenia is the most common cause of dose interruptions/reductions. Responses: All 17 pts have achieved stable disease (SD) or better with overall responses 59%: 9 PR (53%), 7 SD (41%), 1 CR (6%). Responses were reached at a median of 4 months (range 1.8–9.6). No patients have progressed to date. Correlatives: Recent studies have identified cereblon (CRBN) as a direct target of lenalidomide with expression required for anti-tumor activity. CRBN protein was detected by Western blot analysis in CD19-selected cells derived from screening blood samples of all 17 pts evaluated to date and correlation with response is ongoing. Conclusion: Preliminary results from this phase 2 study suggests that lenalidomide plus dexamethasone has significant activity in previously untreated CLL, is generally well-tolerated, and dramatically reduces the incidence of TF symptoms. This may facilitate dose escalation beyond the 10mg daily dose used in our previous single agent study and lead to higher quality responses. Rebound lymphocytosis has not been noted with continuous dosing. Response data are encouraging but whether this combination can achieve durable CR is forthcoming. Disclosures: Chen: Celgene: Honoraria, Research Funding; Lundbeck: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Johnston:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Genotype-Driven Phase I Study of Irinotecan Administered in Combination With Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer

2010 ◽  
Vol 28 (5) ◽  
pp. 866-871 ◽  
Author(s):  
Giuseppe Toffoli ◽  
Erika Cecchin ◽  
Giampiero Gasparini ◽  
Mario D'Andrea ◽  
Giuseppe Azzarello ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Patients With Cancer ◽  
Starting Dose ◽  
Common Grade ◽  
Grade 3 ◽  
Dose Levels ◽  
Higher Doses

PurposeWe aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan.Patients and MethodsPatients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m2for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained.ResultsThe dose of irinotecan was escalated to 370 mg/m2in patients with the *1/*28 genotype and to 420 mg/m2in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m2and in two of three of *1/*1 patients at 420 mg/m2. No DLTs were observed in 10 *1/*28 patients at 310 mg/m2and in 10 *1/*1 patients at 370 mg/m2; hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics.ConclusionThe recommended dose of 180 mg/m2for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.

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