Second-line therapy of KRAS-mutated (KRASm) metastatic colorectal cancer (CRC) with the MEK inihibitor selumetinib ([SEL], AZ6244, ARRY-142886) in combination with irinotecan (IRI): An AGICC study.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 380-380 ◽  
Author(s):  
Howard S. Hochster ◽  
Wells A. Messersmith ◽  
Bert H. O'Neil ◽  
Susan G. Groshen ◽  
Deirdre Jill Cohen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mek Inhibitor ◽  
Median Number ◽  
Dose Finding ◽  
Line Therapy ◽  
Best Response ◽  
Grade 3 ◽  
Gi Bleed ◽  
Number Of Cycles ◽  
Clinical Trial Information

380 Background: 2nd-line therapy of KRASm CRC is limited; targeting downstream signal transduction enzymes is rational here. Use of the MEK inhibitor SEL is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI plus SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin-based chemo + bevacizumab regimen, PS 0-1, acceptable organ function. Patients were treated with IRI 180 mg/m2 iv q2w and SEL 50-75 mg po bid. First 3 patients of run-in portion were treated with SEL 50 mg and if no DLTs, next 3-6 patients at 75 mg po bid. If no DLTs, then phase II dose of SEL 75 mg po bid would be used. Primary endpoint was RECIST 1.0, investigator determined response rate (RR). As compared to the historical RR of 4% (and median PFS 2.5 mos) for 2nd-line FOLFIRI (Tournigand), with alpha 0.10 & beta 0.90, a sample size of 45 would have the power to detect improvement in RR to 15%, and 79% power to demonstrate improved med PFS to 4.0 mos. Early stopping would occur for responses of 0 of 20 patients. Results: 32 patients were entered and treated. Median age was 54 (40-71) yrs, 18 were male and 22 Caucasian, all KRASm. The first 3 tolerated SEL 50 mg bid without SAE and the remaining 29 were treated at 75 bid. Median number of cycles on study was 3.5 and median TTP approximately 4.0 months. Observed grade 3 AEs included: diarrhea 3, fatigue 2, neutropenia 2, and 1 each PLTS, enteritis, GI bleed, rash; one grade 4 ANC. Grade 2 AEs: diarrhea 12, rash 8 pts. Best response (investigator reported) included 3 (9%) confirmed PR and 15 (47%) SD [including 2 unconfirmed PR] of 32 entered. Six patients were on study for > 6 months (6, 6, 8, 9, 12.5, 14.5 months). The study was terminated early due to non-protocol considerations. These data are not yet verified. Conclusions: Despite early termination, the higher RR and PFS noted for 32 patients with KRASm CRC treated with IRI and SEL as 2nd-line therapy of CRC (and treated for up to 14.5 months), are promising compared with historical controls. The strategy of MEK inhibition in KRAS mutated CRC should be explored further. Clinical trial information: NCT01116271.

The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3587-3587 ◽  
Author(s):  
Howard S. Hochster ◽  
Wells A. Messersmith ◽  
Bert H. O'Neil ◽  
Susan G. Groshen ◽  
Heinz-Josef Lenz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mek Inhibitor ◽  
Median Number ◽  
Dose Finding ◽  
Second Line ◽  
Stage Design ◽  
Line Therapy ◽  
Grade 3 ◽  
Gi Bleed ◽  
Number Of Cycles

3587 Background: There are few therapies for second-line KRASm CRC. Inhibiting downstream signal transduction may offer therapeutic options. Use of selumetinib (MEK 1/2 inhibitor; AstraZeneca) is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI + SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin + bevacizumab regimen; PS 0-1; acceptable organ function. Patients (Pts) were treated with IRI 180 mg/m2 iv q2w and SEL 50 or 75 mg po bid. Dose escalation was traditional 3+3 (50 mg bid SEL, then 75 mg bid). In Part B/phase II, primary endpoint was PI-determined response rate (RR) by RECIST. A Simon 2-stage design allowed expansion to 45 pts if ≥1 responses in 20 pts was seen; ≥4/45 responses would be encouraging, when compared to historical RR of 4% (and median PFS 2.5 mo) [EPIC, Sobrero 2008], with approximately 90% power to detect an ORR of 15% at the 10% alpha level (one-sided). Results: N =32 pts entered; 31 treated. Median age was 54 (27-75) yrs; 18 male and 24 Caucasian. The first 3 pts tolerated SEL 50 mg bid without DLT and the remaining 28 were treated at 75 bid. Median number of cycles on study was 3.5 and median PFS was 3.4 mo. Grade 3 AEs included (N): diarrhea 3, fatigue 2, neutropenia 2, and 1 each thrombocytopenia, enteritis, GI bleed, rash. There was one Grade 4 neutropenia. The best PI-reported response included 3 (10%) confirmed PR and 16 (52%) SD [including 1 unconfirmed PR]. 6 patients were on study for more than 6 (up to 22) months. The study was terminated early due to non-protocol considerations. Conclusions: In this small study, the RR of 10% and med PFS of 3.4 mo in pts with KRASm CRC treated with IRI + SEL in 2nd line are promising compared with prior studies in non-selected patients. MEK inhibition in KRASm CRC should be explored further. Supported in part by AstraZeneca.

Biweekly cetuximab and irinotecan as second-line therapy to patients with platinium-resistant gastroesophageal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15624-e15624 ◽  
Author(s):  
J. K. Bjerregaard ◽  
K. R. Schønnemann ◽  
H. A. Jensen ◽  
L. W. Vestermark ◽  
T. P. Hansen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Performance Status ◽  
Haematological Toxicity ◽  
Median Number ◽  
National Board ◽  
Line Therapy ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Cost

e15624 Background: There is no established 2nd line therapy for patients (pts) with advanced gastroesophageal (GE) cancer. In 2004, the Danish government initiated a national health programme for pts with advanced cancer. Non- proven therapy may be offered after approval by an expert panel appointed by the National Board of Health that subsequently finances the cost of treatment. This programme has had a major impact on the management of cancer pts in Denmark and has accelerated the introduction and implementation of new therapies. Inspired by the excellent results in colorectal cancer a combination of cetuximab and irinotecan (CetIri) was chosen for platinum-resistant GE cancer. While awaiting approval of a phase II protocol CetIri was offered at a single institution. We report our preliminary experience with biweekly CetIri as 2nd line therapy in pts with GE cancer. Methods: All pts had histologically confirmed GE cancer (adeno- or squamous cell carcinoma) and all pts had previously received first line platinum based therapy. Pts received CetIri (cetuximab 500 mg/m2and irinotecan 180 mg/m2day 1) every 2nd week until progression or unacceptable toxicity. Response rate was evaluated by the investigator according to RECIST every 8th week. Toxicity was prospectively evaluated according to NCIC-CTC 3.0. Results: From December 2007 to August 2008, 31 consecutive pts was treated with CetIri. Median age was 62 years (33–76). Median performance status was 1 (0–2). Localisation of primary was: Esophagus 10%, GE junction 64%, gastric 26%. Twenty-seven pts (87%) had adenocarcimona. Median number of cycles were 6 (1–21). Most important grade 2–4 toxicities were non-haematological toxicity as diarrhea (25%), nausea (21%) and vomiting (11%). Three pts (11%) had grade 3 leukopenia, 1 had febrile neutropenia. Two pts had PR. Median PFS was 3.2 months. Fourteen pts (45%) received at least 6 courses (3 month of therapy). After a median follow-up of 6 month 5 pts continue CetIri without sign of PD. Conclusions: Biweekly CetIri is a convenient and well-tolerated 2nd line regimen in pts with GE cancer. Predictive factors are needed to select which pts will benefit from therapy. A confirmatory phase II study is ongoing. [Table: see text]

BTTC08-01: A phase II study of bevacizumab and erlotinib after radiation therapy and temozolomide in patients with newly diagnosed glioblastoma (GBM) without MGMT promoter methylation.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2019-2019 ◽  
Author(s):  
Jeffrey J. Raizer ◽  
Pierre Giglio ◽  
Jethro Lisien Hu ◽  
Morris D. Groves ◽  
Ryan Merrell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Number ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Post Radiation ◽  
Grade 3 ◽  
Number Of Cycles ◽  
The Brain ◽  
Worse Prognosis ◽  
Clinical Trial Information

2019^ Background: Patients (pts) with GBM with unmethylated MGMT have a worse prognosis than those with methylated MGMT. Novel approaches for this poor risk group are warranted. The Brain Tumor Trials Collaborative (BTTC) performed a phase II trial evaluating standard chemoradiation followed by bevacizumab and erlotinib in patients with MGMT unmethylated GBM. EGFR and VEGFR are upregulated during radiation suggesting that this combination could be more effective than post-radiation adjuvant temozolomide (TMZ). Methods: After informed consent, adult patients with supratentorial GBM, KPS ≥ 70 and > 1 cm2 tumor block for MGMT promoter analysis were screened. Only tumors with confirmed unmethylated MGMT promoter were enrolled. All patients received RT + TMZ and then approximately 4 weeks after RT they received bevacizumab 10 mg/kg every 2 weeks and erlotinib 150 mg/day, continuously. One cycle was 4 weeks; evaluation by MRI was every 2 cycles. Treatment continued until disease progression or intolerable adverse events. Results: 115 patients were screened; 48 were enrolled (2 unevaluable: 1 for an infratentoral GBM and 1 withdrew after 7 days of treatment) with 29 men, 17 women. Median age was 56 yrs (29-75); median KPS was 90 (70-90). The median number of cycles was 8 (2-38) with 4 patients remaining on trial at the time of analysis. Objective responses: 4 CR, 12 PR and 30 SD. Median PFS is 7.3 months (95% CI (6.4, 11)) and median OS 14.2 months (95% CI (10.7, not reached)). There were no unexpected toxicities; grade 3/4 rate < 5%. Conclusions: Adjuvant bevacizumab and erlotinib in GBM with unmethylated MGMT is well tolerated. Preliminary efficacy data is comparable with outcomes in similar unmethylated MGMT patient populations from the EORTC/NCIC and RTOG 0525 studies. Tissue correlation is being performed. Clinical trial information: NCT00720356.

scholarly journals Phase I clinical trial of the combination of eribulin and everolimus in patients with metastatic triple-negative breast cancer

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Jin Sun Lee ◽  
Susan E. Yost ◽  
Suzette Blanchard ◽  
Daniel Schmolze ◽  
Hongwei Holly Yin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles

Abstract Background Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. Methods The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). Results Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0–8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). Conclusion Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. Trial registration ClinicalTrials.gov, NCT02120469. Registered 18 April 2014

Irinotecan monotherapy as second-line treatment in advanced pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15111-15111 ◽  
Author(s):  
Y. Park ◽  
S. Yi ◽  
H. Kim ◽  
S. Lee ◽  
I. Hwang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stable Disease ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Median Number ◽  
Line Treatment ◽  
Second Line ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles

15111 Background: The aim of this phase II study was to determine whether second line therapy with single agent irinotecan could provide any clinical benefit in patients with gemcitabine- pretreated advanced pancreatic cancer. Methods: From January 2004 to October 2006, patients with advanced pancreatic cancer previously treated with gemcitabine alone or combination were treated with single agent irinotecan(150 mg/m2, biweekly), until unacceptable toxicity or disease progression. Primary endpoint was response rate with single stage design. Results: Twenty-eight patients were enrolled(22 male, 6 female, median age : 54.5 years (39–76)). Nine patients are still alive and 3 remain on therapy with stable disease. The median number of cycles was 3.5(1–12). Twenty-four patients were assessable for toxicity and 21 for response. The most common toxicities was diarrhea (grade 3, 12.5%). Grade 3 neutropenia in 1 patient was observed. Other hematological and non-hematological toxicities were mild and manageable. Partial responses were observed in 3 patients (3/21, 14%). An additional 9 patients (9/21, 43%) had stable disease as their best response. 12 patients have progressed with a median time-to-progression of 4.0 months. Conclusions: Single-agent irinotecan was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced pancreatic cancer, refractory to gemcitabine. No significant financial relationships to disclose.

A randomized phase II study of perifosine (P) plus imatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10563-10563 ◽  
Author(s):  
A. P. Conley ◽  
D. Araujo ◽  
J. Ludwig ◽  
V. Ravi ◽  
B. L. Samuels ◽  
...  
Keyword(s):  
Phase Ii ◽  
Median Number ◽  
Blurred Vision ◽  
Imatinib Resistance ◽  
Choi Criteria ◽  
Grade 3 ◽  
Exon 11 ◽  
Number Of Cycles ◽  
Ecog Ps ◽  
Advanced Gist

10563 Background: P inhibits activation of the Akt pathway which results in apoptosis and block cancer cell proliferation. Since AKT is a molecule downstream of Kit, its inhibition may overcome Kit-dependent imatinib resistance. We performed a phase II trial to assess antitumor activity of perifosine in patients with advanced GIST who were refractory to imatinib mesylate. Methods: Pts with Kit(+) advanced GIST who have PD on IM were eligible. Pts continued their current dose of IM and were randomized to one of two dosing schedules of P (Arm A: 100 mg p.o. qd x 28 + IM or Arm B: 900 mg [300 mg p.o tid] qweekly + qd IM). A Bayesian approach was utilized to assess a target response rate or 20% with an unacceptable toxicity rate of 15% or less. Response was measured at q8 wk intervals by RECIST and Choi criteria. The primary endpoint was to determine the efficacy of P with IM in pts with advanced GIST with PD while receiving IM. Results: From 8/2005 to 7/2008, 41 pts were accrued. After 1 pt exclusion and 2 cross-overs, 22 pts were in Arm A and 18 pts in Arm B. Median age was 58 (range, 32–82), 51% were male, and median ECOG PS was 1. The most common primary site of disease and metastasis was the stomach (29%) and liver (66%), respectively. KIT genotype was available for 22 pts(54%); 5(12%) WT, 13(32%) exon 11 mutations, and 4(10%) exon 9 mutations. The median number of cycles was 2 (range, 1–24). By Choi and RECIST, 30 pts(73%) and 36 pts(87%) were available for response, respectively. No CR was identified but the PR rate was 4/36 (11%) by Choi (4 PR, 9 SD) and 0/36 (0%) by RECIST (16 SD). 4/5 (80%) of pts with WT KIT appeared to benefit (Choi: 1 PR, 3 SD; RECIST: 4 SD). Median PFS and OS for 40 pts were 2.2 months and 18.3 months. No difference in PFS was noted for the 2 schedules. Toxicity was assessed in 39 pts; 46 grade 3 events and 4 grade 4 events (ALT elevation, blurred vision, fatigue, and mood alteration) were noted. The most common grade 3 event was fatigue (20%). Three pts (7%) were removed from the study for toxicity (Arm A:1 pt, Arm B:2 pts). Conclusions: The addition of P to IM has minimal activity in IM-refractory GIST although its activity in GIST with WT KIT may be further investigated. No significant financial relationships to disclose.

Updated results from a randomized phase II dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with myelofibrosis (MF).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7109-7109 ◽  
Author(s):  
Animesh Dev Pardanani ◽  
Catriona H. M. Jamieson ◽  
Nashat Y. Gabrail ◽  
Claudia Lebedinsky ◽  
Guozhi Gao ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Median Number ◽  
Randomized Phase Ii ◽  
Night Sweats ◽  
Dose Ranging ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Dose Reductions ◽  
Unacceptable Toxicity

7109 Background: We previously reported results of treating MF patients with 3 cycles of 300, 400, or 500 mg of SAR302503 (NCT01420770; Blood 2012;120:21 Abs 2837). This is a report of efficacy and safety after 6 cycles. Methods: Patients ≥18 years of age with intermediate-2 or high-risk MF and splenomegaly were eligible. SAR302503 is administered orally, once a day in consecutive 4-week cycles until disease progression or unacceptable toxicity. Spleen response (≥35% reduction in spleen volume vs baseline) was assessed by MRI/CT (blinded independent central review). Results: 31 patients were enrolled (n=10 in the 300 and 400 mg groups; n=11 to 500 mg). Risk status was balanced in all but the 300 mg group (70% high-risk). Most patients were JAK2V617F positive (90%) and blood transfusion independent (81%). Spleen response rates at the end of cycle (EOC) 6 (secondary end point) were 30% (3/10) in the 300 mg group, 60% (6/10) with 400 mg, and 55% (6/11) with 500 mg compared with EOC 3 rates of 30%, 50%, and 64%, respectively. One patient on 500 mg who had a spleen response at EOC 3 (39% reduction), but not at EOC 6 (25% reduction) had dose reductions to 200 mg due to anemia. Median number of cycles was 13 (range, 2–17) and 24 patients have been on treatment >12 months. SAR302503 reduced baseline constitutional symptoms at the EOC 3, with the greatest responses for night sweats in 14/15 patients (93%), itching 10/14 (71%), early satiety and abdominal pain, each in 10/18 (56%). Most common adverse events were anemia and diarrhea, with grade 3–4 rates of 58% and 13%, respectively. The rate of grade 3–4 thrombocytopenia was 16%. There was no grade 3–4 neutropenia. The diarrhea rate tended to decrease after the first 2 treatment cycles. There have been no reports of withdrawal syndrome after stopping SAR302503. Median JAK2V617F allele burden was 93% at baseline, 87% at the EOC 3, and 78% at EOC 6 in 19/26 patients who had available samples. The expression of 22 of 97 cytokines was significantly regulated (≥1.5 fold difference; p<0.05) after cycle 1. Conclusions: In this Phase II trial, continued treatment with SAR302503 was associated with clinically meaningful reductions in splenomegaly. Symptom data will be updated. Clinical trial information: NCT01420770.

Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 433-433
Author(s):  
Matthew T. Campbell ◽  
Randall E. Millikan ◽  
Emre Altinmakas ◽  
Lianchun Xiao ◽  
Nizar M. Tannir
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Primary Objective ◽  
Best Response ◽  
Treatment Naïve ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Mean Time

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

Phase II study of bevacizumab in combination with cisplatin and docetaxel as first-line treatment of patients (p) with metastatic non-squamous non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19023-e19023
Author(s):  
N. Ferrer ◽  
M. Cobo ◽  
A. Paredes ◽  
M. Méndez ◽  
J. Muñoz-Langa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Median Number ◽  
Line Treatment ◽  
Eligibility Criteria ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
Grade 3 ◽  
Number Of Cycles

e19023 Background: Bevacizumab (B), in addition to platinum-based chemotherapy, is indicated for 1st-line treatment of p with advanced NSCLC other than predominantly squamous cell histology. B has been shown to improve progression free survival (PFS) and overall survival (OS) when combined with cisplatin/gemcitabine and carboplatin/paclitaxel, respectively. However, there are limited data on the safety and efficacy of B in combination with other widely used chemotherapy doublets for NSCLC. This is a single-arm, open- labeled, single-stage phase II trial of cisplatin (C), docetaxel (D) and B for NSCLC. Methods: Eligibility criteria: chemo- naïve, stage IIIB wet or IV, non-squamous NSCLC, PS 0–1, no brain metastases and no history of gross hemoptysis. P received D (75 mg/m2), C (75 mg/m2), and B (15 mg/kg iv) on day 1 every 3 weeks for up to 6 cycles, followed by B 15 mg/kg alone every 3 weeks until disease progression or toxicity. Primary endpoint: PFS. Results: 50 p were enrolled (enrollment completed): 24% female, median age 60 (36–74), PS 1: 64%, adenocarcinoma: 72%; stage IV: 92%. Two p did not start treatment. Median follow-up is 5.3 months (range 0–13.6). Median number of cycles of B was 7 (range 0–18). 56% completed 6 cycles of treatment; 24% received ≥ 12 cycles of B. Most frequent grade ≥ 3 toxicities: diarrhea (14.6%), fatigue (14.6%), dyspnea (9.8%), anorexia (4.9%), alopecia (4.9%), esophagitis (4.9%), constipation (4.9%), mucositis (12.2%), proteinuria (4.9%); hematological toxicities: neutropenia (22%), febrile neutropenia (9.8%), leucopenia (14.6%), lymphopenia (4.9%). Of interest, 41.5% developed grade <3 epistaxis and 17% hypertension (1 p grade 3). One p died due to hemoptysis. 46 p were evaluable for response: 29 PRs (ORR: 63%). 18 of 48 p have experienced progression or death with a median SLP of 7.8 months (95% CI: 6.6-NR). Median OS is 13.5 months (95% CI: 12.7–13.6; 81.2% p censored); 1-year survival is 83.9% (95% CI: 67.4%-92.5%). Conclusions: Treatment with C, D and B, followed by maintenance B in 1st line of advanced non-squamous NSCLC shows an acceptable toxicity profile and promising efficacy. Final results will be presented. [Table: see text]

A phase I study of the oral administration of irinotecan in combination with the potent P-glycoprotein (P-gp) inhibitor HM30181A.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3032-3032
Author(s):  
Antonio Jimeno ◽  
Mateusz Opyrchal ◽  
Jennifer Robinson Diamond ◽  
Christos Fountzilas ◽  
Bradley Corr ◽  
...  
Keyword(s):  
Oral Administration ◽  
Dose Level ◽  
Phase 1 ◽  
Median Number ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Best Response ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Pharmacologically Active

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]

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