Skin events (SE) among 1,126 patients (Pts) treated with lapatinib (L), an oral dual ErbB1/2 tyrosine kinase inhibitor (TKI)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9102-9102 ◽  
Author(s):  
R. Sweetman ◽  
M. E. Lacouture ◽  
M. Koehler ◽  
S. Laabs ◽  
A. Preston ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Drug Eruption ◽  
Kinase Inhibitor ◽  
Treatment Time ◽  
Single Agent ◽  
Skin Toxicity ◽  
Drug Discontinuation ◽  
Low Grade ◽  
Tumor Type ◽  
Grade 3

9102 Background: Lapatinib (L) is active as a single agent and in combination with capecitabine in pts with ErbB2+ve breast cancer. Safety profile from > 5,000 pts demonstrates infrequent Grade (G)3/4 (10%) adverse events, with drug discontinuation (disc) required in (<2%) events. SEs were commonly reported and were likely due to ErbB1 inhibition in the epidermis, as hypothesized with the other ErbB1 TKIs. However, the SE with L appear to differ clinically from other TKIs. Methods: SE in 1,126 pts reported in 8 L trials ( EGF20001 , EGF20002 , EGF20003 , EGF20004 , EGF20008 , EGF20009 , EGF20014 , + EGF100151) were pre-defined as dermatitis, drug eruption, dry skin, pruritus/urticaria, skin disorder, skin infection, nail, and hair disorder. SE were characterized based on CTC grading, and examined as to their relationship to L dose, length of L exposure, tumor type, concurrent treatment, time to onset from L initiation, and time to resolution with L dose- reduction or disc. Furthermore clinical management, skin biopsies, photos, and outcome were examined. Results: Pts were treated with L monotherapy 1,000–1,500mg daily (N=928), or in combination with capecitabine (C) (N=198). Non-L containing arms of studies EGF100151 (N=191; C alone) and EGF20001 (N=197; tamoxifen alone) served as controls. Among all L treated pts, 54% experienced SE mostly as G1/2, and 69% L+C pts experienced G1–3 SE with 50% G2. Majority of SE were deemed not specific to L and were rarely severe (no G4). Only 1% required drug disc. Most frequently reported SEs were dermatitis/drug eruption (38% all grade; 3% G3) (8% all grade, 1% G3). The frequency of SE with L at 1,500 mg QD was 57%, 1250 mg QD was 41%, and 500 BID was 63%. Most SE developed early (45% day 1–14) and persisted a median of 29 days. The majority of L pts (82%) did not require intervention (ie, dose reduction, hold, or withdraw). Conclusions: This large collection of L treated pts demonstrates that SE related to L therapy are low grade, infrequently require intervention or dose reduction, and rarely cause drug disc. Further attempts to identify pts at high risk for skin toxicity, its management, and the pathophysiology of L related SE are ongoing. No significant financial relationships to disclose.

scholarly journals LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWING TREATMENT WITH ALTERNATIVE MEK INHIBITOR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii372-iii372
Author(s):  
Margot A Lazow ◽  
Sarah A Lawson ◽  
Ralph Salloum ◽  
Trent R Hummel ◽  
Natasha Pillay Smiley ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Fluid Intake ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Tumor Control ◽  
Low Grade ◽  
Pituitary Dysfunction ◽  
Adequate Understanding ◽  
Pediatric Patient Population ◽  
Inhibitor Combination

Abstract Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.

scholarly journals Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial

2013 ◽  
Vol 31 (11) ◽  
pp. 1405-1414 ◽  
Author(s):  
Athanassios Argiris ◽  
Musie Ghebremichael ◽  
Jill Gilbert ◽  
Ju-Whei Lee ◽  
Kamakshi Sachidanandam ◽  
...  
Keyword(s):  
Head And Neck ◽  
Disease Progression ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Single Agent ◽  
Eastern Cooperative Oncology Group ◽  
Phase Iii ◽  
Oncology Group ◽  
Ecog Performance Status ◽  
Grade 3

Purpose We hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN). Patients and Methods Patients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing. Results Two hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response. Conclusion The addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.

SDX-105 Demonstrates a High Response Rate as a Single-Agent with Acceptable Safety in Rituximab-Refractory, Relpased Indolent or Transformed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2480-2480 ◽  
Author(s):  
Jonathan Friedberg ◽  
Philip Cohen ◽  
Robert O. Kerr ◽  
K. Sue Robinson ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Reduction ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Mitotic Catastrophe ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Cell Death Pathway ◽  
Grade 3

Abstract SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of &gt;50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated, Stage III or IV, Low-Grade B-Cell Non-Hodgkin’s Lymphoma (NHL) or Bulky Stage II Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1354-1354
Author(s):  
Raul R. Mena ◽  
Neil P. Christiansen ◽  
Yudhishtra Markan ◽  
Lalita Pandit
Keyword(s):  
Febrile Neutropenia ◽  
B Cell ◽  
Single Agent ◽  
Stage Ii ◽  
Stage Iii ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Purine Analog ◽  
Previously Treated ◽  
Grade 3

Abstract The decision to treat indolent B-cell NHL is often based on progression of the disease. Most regimens have utilized fludarabine as the purine analog but the myelosuppression and immunosuppression of fludarabine combinations frequently results in severe infections. Combination therapy with pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, based on the single-agent activities, documented synergy, and non-overlapping toxicity profiles, may represent a promising approach in the treatment of these patients. To further investigate the efficacy of the PCR regimen for the treatment of indolent NHL, we conducted a phase II study. Patients diagnosed of bulky stage II, stage III/IV low-grade NHL (REAL classification), previously untreated or treated, were eligible. All patients were treated with intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for at least 8 cycles. 2 additional cycles were given for patients with PR or SD after cycle 8 or patients with CR/CRu first evident at cycle 8. Clinical evaluation was performed after cycles 2, 4, 6, 8, and 10 if necessary. Dose modification for hematologic toxicity may be increased to the previous higher level when a hematologic toxicity returned to normal. Two 25% dose reductions or one 50% dose reduction were allowed for nonhematologic toxicity. One hundred patients with indolent NHL, 68 previously untreated, 26 previously treated, and 6 with unknown treatment history, were enrolled in the study. The median age was 61 years (range 29–84) and 63.4% were ECOG PS 0, 36.6% PS1. A total of 550 cycles were given, with a median of 6 cycles per patient. 8 patients were not evaluated for response due to withdrawal of consent (n=1), unacceptable toxicities (n=3), and missing data (n=4). 92 patients received at least two cycles of treatment and were evaluated for response. The highest response rate (RR) achieved was 68%, with 10 (10%) CR, 12 (12%) CRu, 46 (46%) PR, 23 (23%) SD, and 1 (1%) disease progression. Stratified according to previous treatment status, patients with previously untreated NHL had an RR of 47% (CR, CRu 17%) while that of the previously treated was 17% (CR 7%). 14 (14.0%) patients discontinued treatment due to toxicities. Grade 3/ 4 hematological adverse events documented included 10 grade 4 and 16 grade 3 neutropenia. Infectious complications were noted in 8 patients including 3 grade 3 febrile neutropenia, 2 grade 4 febrile neutropenia, and 3 grade 3 infections. A total of 4 deaths were recorded, including 1 due to acute myocardial infarction, 1 suspected cardiac event and 2 unknown causes. This immunochemotherapeutic regimen is active in patients with indolent NHL. The study is currently on-going and updated results will be presented.

Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 919-919
Author(s):  
Steven M. Horwitz ◽  
Madeleine Duvic ◽  
Youn Kim ◽  
Jasmine M Zain ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Dose ◽  
T Cell Lymphoma ◽  
Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

Patterns Of Non-Hematological Adverse Effects In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Treated With Ponatinib – Experience At a Single Institution

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4019-4019 ◽  
Author(s):  
Preetesh Jain ◽  
Hagop M. Kantarjian ◽  
Carlos Guillermo Romo ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Risk Factors ◽  
Adverse Effects ◽  
Dose Reduction ◽  
Research Funding ◽  
Skin Toxicity ◽  
Qtc Prolongation ◽  
Single Institution ◽  
Dry Skin ◽  
Starting Dose ◽  
Grade 3

Abstract Introduction Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) efficacious in pts with refractory CML. Ponatinib inhibits other tyrosine kinases (e.g. RET, FGFR, FLT3) that may lead to off target adverse effects (AE). We report a single-institution experience of frequencies of non-hematological AE among pts on therapy with ponatinib. Methods A total of 90 pts with CML-CP[49 relapsed refractory (RR), 41 frontline] treated at our institution on clinical trials with ponatinib were analyzed. AE were recorded on each pt visit and charts were reviewed for AE and risk factors. Results For RR pts (n=49)the starting dose of ponatinib was 45 mg in 42 (86%) pts. 39 (80%) had dose interruptions, due in 17 (44%) to grade 3 thrombocytopenia and in 22 (56%) to non-hematological AE (elevated pancreatic enzymes 7 pts of whom 5 had pancreatitis; body aches and headache 7; hypertension 7; skin toxicity 5; fatigue 5). 35 pts (71%) had dose reduction to 30 or 15 mg. Hypertension (H.T.) stage 2 (≥160/100 mm Hg) occurred in 15 (31%) pts; only 2 of new onset. Blood pressure was controlled in all with antihypertensives. Other cardiovascular AE included QTc prolongation in 1 pt, atrial fibrillation in 1 pt, acute myocardial infarction in 3, venous thrombosis in 3, arterial thrombosis in 4, transient ischemic attack (TIA) in 1 and Raynaud’s in 1. No pt discontinued ponatinib due to cardiovascular AE’s. Symptomatic pancreatitis developed in 8 pts (16%). Grade 3/4 elevations in serum lipase and amylase occurred in 12 (24%) pts and 2 (4%) pts respectively. Median days to onset of pancreatitis was 24 (range 7-456). 27 pts (55%) developed cutaneous toxicity including xerosis/dry skin in 10 (37%) and grade 3 erythroderma and exfoliation of the skin in 5. Four pts died, none related to ponatinib. 13 pts went off the study: 5 went to SCT, 3 progressed, 1 pt died in CCyR of multiple co-morbidities, 1 pt had progressive melanoma, 1 pt was transferred to another hospital, and 2 for ponatinib-related AE (headache in 1 and headache, fatigue, depression, and abdominal pain in 1). For pts in frontline setting (n=41) the starting dose was 45 mg in all. 29 pts (71%) had dose interruptions due to one or more of the following: grade 3/4 pancreatic enzyme elevation in 16, myelosuppression in 4, and various non-hematological AE in 15 (skin toxicity in 4, fatigue in 2, headache in 1, chest pain in 2, elevated liver enzymes in 2, suspected seizure vs. TIA in 1, grade 3 diarrhea in 1, memory disturbances in 1, and grade 3 hypertension in 1, erectile dysfunction in 1). 24 pts (59%) had dose reduction, from 45 mg to 30 mg in 20 pts and then to 15 mg in 4 pts. H.T. stage 2 occurred in 3 (7%) pts usually among patients with pre-existing H.T. Other cardiovascular AE included grade 2 QTc prolongation in 1 pt, possible TIA vs. possible seizure in 1, and Raynaud’s in 2. Pancreatitis was seen in 12 pts (29%) with grade 1-2 and 6 pts (15%) with grade 3/4. Grade 3/4 lipase/amylase elevations occurred in 16 (39%) and 3 (7%) pts. Median days to the onset of pancreatitis were 6 (4-22). 34 pts (83%) developed skin toxicity with rash (any grade) in 25 pts (61%), xerosis/dry skin in 18 pts (44%) and grade 3 erythroderma and skin exfoliation in 2 (pts may have had ≥1 type of skin AE). 2 pts discontinued therapy, due to severe xerosis in 1 and recurrent gra 4 neutropenia in another. 1 pt developed grade 2 pericarditis possibly related to ponatinib. For all the 90 pts, risk factors for cardiovascular and pancreatic toxicities included 20 (22%) smokers, 2 heavy alcohol consumers, 27 (30%) obese (BMI ≥30 Kg/m2), 30 (33%) with hypertriglyceridemia, 17 (19%) had hypercholesterolemia and 10 pts were receiving lipid lowering therapies. Conclusions Ponatinib is generally well tolerated and AEs can usually be properly managed. AE are more common in RR pts with greater frequency of hypertension, cardiovascular complications, headache, dry mouth and dose interruptions. Most pts are able to continue therapy after dose adjustments. Disclosures: Kantarjian: ARIAD: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

First-line single-agent cetuximab in patients with advanced colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3553-3553 ◽  
Author(s):  
A. Pessino ◽  
S. Artale ◽  
A. Guglielmi ◽  
S. Sciallero ◽  
G. Fornarini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Great Majority ◽  
Skin Toxicity ◽  
Common Adverse Event ◽  
Time To Progression ◽  
Grade 3

3553 Background: The most relevant recent advance in the treatment of metastatic colorectal cancer is the fact that cure is still possible under very selected conditions. However the goal of chemotherapy remains palliative in the great majority of patients, justifying less toxic innovative approaches in so- called “window of opportunity trials”. We have pursued this idea in a phase II study of cetuximab monotherapy in chemo-naive patients with advanced colorectal cancer beyond any possibility of curative resection. Methods: Patients with non-resectable metastatic colorectal cancer (at least two metastatic sites and/or otherwise inoperable metastatic disease) were treated with cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) until progressive disease (PD) or unacceptable toxicity. The primary end-point was objective response; secondary end-points were: stable disease, time to treatment failure and time to progression. According to Simon’s two-stage design, the number of responses/patients to stop the trial was 0/10 for stage 1 and 3/29 for stage 2. Results: Of the 44 patients screened, 42 (97%) had EGFR-expressing tumors. Thirty-nine patients (median age: 69) initiated the treatment. Two had grade 3 allergic reactions to cetuximab at the first administration leading to treatment discontinuation. The most common adverse event was skin toxicity, which occurred in 90% of the patients ( 31% grade 2, 10 % grade 3). We observed 1 complete response, 3 partial responses, 13 stable diseases (5 of which were minor responses), and 22 PD. The duration of the 4 responses were 12, 9, 9 and 6 months. Median time to progression was 2.0 months. Conclusions: The study is negative because the response rate is low. However, the duration of benefit in the few responding patients is such that it is imperative to find the molecular determinants of cetuximab activity in these cases. [Table: see text]

A phase I pharmacokinetic (PK) and molecular pharmacodynamic (PD) study of the combination of two anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts) with advanced colorectal (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3006-3006 ◽  
Author(s):  
J. Baselga ◽  
P. Schöffski ◽  
F. Rojo ◽  
H. Dumez ◽  
F. J. Ramos ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Gene Profiling ◽  
Clinical Activity ◽  
Skin Biopsies ◽  
Grade 3 ◽  
Development Methods ◽  
Further Development ◽  
Profiling Analysis ◽  
Different Doses

3006 Background: C and G are two anti-EGFR agents with different mechanisms of action. We had previously shown a synergistic effect combining the two agents in preclinical models (Matar et al, Clin Cancer Res 2004). This study aims to explore safety, PK and PD changes in tumor and skin at different doses of C/G to define the recommended dose (RD) for further development. Methods: pts were treated at the RD of weekly iv C (400 mg/m2 initial dose, 250 mg/m2 weekly) and oral daily G (250 mg/d) as single agents (5 pts each) and in successive cohorts of combined C/G (3–6 pts each): C (320/200) / G (100), C (400/250) / G (100), C (400/250) / G (250), C (320/200) / G (500) & C (400/250) / G (500) (ongoing). Dose escalation depended on dose limiting toxicity (DLT) rate during the first 28 d. Pre- & on-treatment steady-state (14 d) tumor & skin biopsies were obtained and have been evaluated by IHC for total (t) and phospho (p)-EGFR, p-MAPK, p-Akt, proliferation (Ki67), p27 expression and apoptosis by TUNEL. Gene profiling analysis is ongoing. Results: 35 pts have been treated so far: 20 CRC, 13 HNC & 2 NSCLC; median KI 90 % (70–100); median age 60 years (38–80); 24 males, 11 females. DLTs occurred in 3 pts: 1 pt with G alone with reversible ILD; 1 pt with G (250) / C (400/250) with reversible deafness & 1 pt with G (500) / C (320/200) with grade 3 anorexia and nausea. There were 1 CR (HNC) and 5 PRs (CRC) in the C/G cohorts, and 1 PR (CRC) in the C cohort. Overall, 5 out of 9 (56%) pts with CRC treated in the C/G cohorts presented a PR. PD studies show superior inhibition of p-EGFR, p-MAPK and p-Akt, reduction of proliferation and increased apoptosis (all p values <0.05) in the tumors of pts treated with C/G compared with the single agent cohorts. PK evaluation shows no PK interactions with the 2 drugs. Conclusions: This combination of an anti-EGFR MAb (C) and a TKI (G) is feasible at the RD of both agents. Our findings show encouraging clinical activity, especially in CRC, and superior PD signaling inhibition with the combination without any significant PK interaction. Combined anti-EGFR therapy deserves further evaluation. [Table: see text]

A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1003-1003 ◽  
Author(s):  
H. S. Rugo ◽  
A. Stopeck ◽  
A. A. Joy ◽  
S. Chan ◽  
S. Verma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Single Agent ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Hazard Ratio ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Grade 3

1003 Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity. No significant financial relationships to disclose.

Sunitinib malate (SU) plus interferon (IFN) in first line metastatic renal cell cancer (mRCC): Results of a dose-finding study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5101-5101 ◽  
Author(s):  
G. V. Kondagunta ◽  
G. R. Hudes ◽  
R. Figlin ◽  
G. Wilding ◽  
S. Hariharan ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Cell Cancer ◽  
Single Agent ◽  
Dose Finding ◽  
First Line ◽  
Sunitinib Malate ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor ◽  
Dose Modifications

5101 Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs with anti-tumor activity in mRCC patients previously treated with cytokines (JAMA, 2006;295:2516). A phase 3 randomized trial showed superiority for SU over IFN in first-line mRCC (PROC ASCO 24,18S, 2006). Dose and safety for SU combined with IFN was investigated in this phase I trial. Methods: Patients (pts) with previously untreated clear-cell mRCC received SU in repeated 6-week cycles of 50 or 37.5 mg/day orally for 4 weeks, followed by 2 weeks off treatment. IFN was given continuously, starting at 3 MU SC 3x/week with intrapatient dose escalation weekly as tolerated, to a maximum of 9 MU. Pts not tolerating a dose combination received lower doses of SU or IFN, or had dose interruptions. Doses of SU plus IFN were considered tolerable if = 4/6 pts completed 2 cycles without dose reduction or interruption. Results: 25 pts were enrolled; 19 are evaluable for safety/response. 6 pts who started treatment at 37.5 SU and 3 MU IFN are too early. The median age of the 19 pts (16 M: 3 F) was 63 years (range 45–77). MSKCC risk group (JCO 20:289–96, 2002) was 37% good and 63% intermediate. 12 pts started treatment with SU 50 mg and dose escalated IFN to 6 or 9 MU TIW. 13 pts started treatment with SU 37.5 mg and dose escalated IFN at 3 MU or to 6 MU TIW. 4 of 19 pts tolerated two cycles. 68% of pts had dose interruptions of SU; 90% of pts had dose interruptions of IFN. 15/19 pts had grade 3 toxicity, 1 pt had grade 4 hypertension and 1 pt grade 5 toxicity (myocardial infarction). Most common grade 3 toxicities were neutropenia (26%), fatigue (26%), and hand-foot syndrome (16%). Although response was not a primary endpoint, at a median of 3 cycles, there were 2 PR, 14 SD, 2 PD and 1 pt was not evaluable. Conclusions: The adverse events seen with combination SU and IFN in mRCC, neutropenia and fatigue, were similar to those seen with single agent SU and IFN, and resulted in frequent dose modifications and interruptions. The safety and efficacy of 37.5 mg sunitinib and 3 MU IFN is being evaluated. No significant financial relationships to disclose.

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