Phase I trial of ALT-801, a first-in-class T-cell receptor (TCR)-interleukin (IL)-2 fusion molecule, plus gemcitabine (G) for Bacillus Calmette Guerin (BCG)-resistant non-muscle-invasive bladder cancer (NMIBC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 451-451 ◽  
Author(s):  
Guru Sonpavde ◽  
Charles Joel Rosser ◽  
Chong-xian Pan ◽  
Rahul Atul Parikh ◽  
Jeffrey Nix ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Phase I Trial ◽  
Response Assessment ◽  
Complete Response ◽  
Cell Receptor ◽  
Clinical Activity ◽  
Maintenance Cycle ◽  
Step Down ◽  
Grade 3

451 Background: Novel agents are necessary to treat BCG-resistant NMIBC to avoid radical cystectomy (RC). This phase I clinical trial evaluated the safety and activity of ALT-801, a recombinant humanized TCR-IL-2 fusion protein in BCG-resistant NMIBC. Methods: This is a Phase I trial using the 3+3 design to evaluate intravenous (IV) ALT-801 plus IV G 1000 mg/m2 in BCG-resistant high-risk NMIBC patients (pts) defined as high grade Ta, T1 or carcinoma in situ, size > 4 cm or multi-focal tumors. BCG-intolerant pts, those who refused or were unfit to undergo RC were also eligible. Initially, patients received ALT-801 monotherapy; an amendment added G. Pts received induction of 2 cycles, with a 13-day rest between cycles. Each cycle consisted of 4 doses of ALT-801 on Day 3, Day 5, Day 8, and Day 15 and 2 doses of G, one each on Day 1 and Day 8. Pts who have a biopsy-proven complete response (CR) after induction received one maintenance cycle and underwent response assessment. The initial dose of ALT-801 was 0.08 mg/kg with 2 step-down doses allowed if dose limiting toxicities (DLTs)- 0.06 mg/kg and 0.04 mg/kg. Results: 2 pts in cohort one received ALT-801 alone at 0.08 mg/kg per dose, a 3rd pt received G and ALT-801 at 0.08 mg/kg per dose. Grade ≥ 3 hepatotoxicity in the 3rd patient led to a step-down to 0.06 mg/kg dose. One pt in the 0.06 mg/kg dose experienced a DLT (Grade ≥ 3 hepatotoxicity) and the cohort was expanded to 6 pts with no further DLTs. Other attributed adverse events were: anorexia, pruritus, rash, edema, fatigue, chills. For the 0.06 mg/kg ALT-801 + G regimen, 6 pts received up to 2 cycles of induction and 4 pts received the maintenance cycle. All pts have completed therapy without further DLTs. CR was observed in 3 pts, which was durable in 2 pts lasting ≥ 18 months. Preliminarily immune studies have shown transient IFN-γ and IL-6 but not TNF-α and IL-10 induction after ALT-801 dosing. Conclusions: ALT-801 plus gemcitabine was feasible in BCG-resistant NMIBC and demonstrated immune responses and potential durable clinical activity. Further evaluation in expansion cohorts in a phase Ib/II trial is planned. Clinical trial information: NCT01625260.

Phase I Clinical Trial of the Anti-CD22 Immunotoxin CAT-8015 (HA22) for Pediatric Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 839-839 ◽  
Author(s):  
Alan S. Wayne ◽  
Deepa Bhojwani ◽  
Sima Jeha ◽  
Maryalice Stetler-Stevenson ◽  
Ching-Hon Pui ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Pleural Effusion ◽  
Phase I ◽  
Phase I Trial ◽  
Tumor Lysis Syndrome ◽  
Clinical Activity ◽  
Vascular Leak Syndrome ◽  
Vascular Leak ◽  
Grade 3 ◽  
B Lineage

Abstract Abstract 839 Although most children with ALL are cured, treatment is associated with multiple toxicities and outcome after relapse is poor. New therapies are needed to overcome drug resistance and reduce non-specific toxicities of chemotherapy. CD22 is a B-lineage differentiation antigen expressed on most B-lineage ALL blasts. The anti-CD22 immunotoxin RFB4(dsFv)-PE38 CAT-3888 (BL22) was recently shown to have clinical activity with an acceptable safety profile in children with ALL (Blood 2007;110:262a). We undertook a Phase I trial of a modified agent with higher CD22 binding affinity (CAT-8015 or HA22). Methods: Patients 6 months to 24 years of age with relapsed or refractory CD22 + B-lineage ALL or non-Hodgkin lymphoma were eligible for enrollment into this Phase I trial. CAT-8015 was administered at doses of 5, 10, 20, or 30 mcg/kg every-other-day for 6 doses every 21 days for up to 6 cycles. One patient was enrolled at each of the first 3 dose levels (5, 10, 20 mcg/kg) with standard 3+3 dose escalation commencing at 30 mcg/kg. All patients received acetaminophen, ranitidine and diphenhydramine to mitigate infusion-related symptoms, and prophylaxis for central-nervous-system leukemia with intrathecal hydrocortisone, cytarabine and methotrexate. Patients at high risk for tumor lysis syndrome received standard prophylaxis. Results: Seven patients with ALL (6 precursor-B, 1 mature B-cell) 5 to 17 years of age (median, 10) were treated on the clinical trial. All patients had been heavily pre-treated and had baseline cytopenias due to active malignancy and thus were not evaluable for hematologic toxicities. The most common adverse events observed to date have been hyperbilirubinemia, transaminase elevations, hypoalbuminemia, elevated creatinine, febrile neutropenia, abdominal pain, pyrexia, hypertension, microscopic proteinuria, hemoglobinuria, hypoxia and pleural effusion. Two of 4 patients treated at 30 mcg/kg experienced Grade 3 or greater toxicity consistent with capillary leak: 1 with Grade 3 pleural effusion and hypoxia and 1 with Grade 4 vascular leak syndrome. All toxicities attributed to CAT-8015 were reversible. Clinical activity was demonstrated in 4 of 7 subjects. One patient treated at 10 mcg/kg had a complete remission by morphology and flow cytometry. Three patients met the protocol definition for hematologic activity (blood count improvement). One of these patients developed high-titer neutralizing antibodies. Two patients met the protocol definition for stable disease. The patient treated at the lowest dose level had progressive disease. Conclusions: CAT-8015 appears to be active against chemotherapy-refractory ALL. Strategies to predict and/or prevent vascular leak syndrome are currently being developed. Disclosures: No relevant conflicts of interest to declare.

A Phase I Trial of Two Sequence-Specific Schedules of Decitabine and Vorinostat in Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 908-908 ◽  
Author(s):  
Karen W.L. Yee ◽  
Mark D. Minden ◽  
Joseph Brandwein ◽  
Aaron Schimmer ◽  
Andre Schuh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Concurrent Schedule ◽  
Maximum Tolerated Dose ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Sequential Schedule ◽  
Grade 3

Abstract Background: Epigenetic silencing of genes has been documented in AML. This phase I trial evaluates the safety, tolerability, and maximum tolerated dose (MTD) of two schedules of administration of the hypomethylating agent decitabine in combination with the pan-selective histone deacetylase inhibitor vorinostat. Methods: Patients receive escalating doses of oral vorinostat administered either sequentially [100 mg bid (n=4), 200 mg bid (n=4), or 200 mg tid (n=8) Days 6–21] or concurrently [100 mg (n=3) or 200 mg (n=6) bid Days 1–21 or 200 mg tid (n=2) Days 1–14] with decitabine (20 mg/m2/d IV Days 1–5) every 28 days. Results: Twenty-seven patients with AML have been treated. Median age was 67 years (range, 32–82 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (67%) had received prior therapy (median, 1 regimen; range, 0 to 4 regimens); 3 had received a prior allogeneic stem cell transplant. A total of 85 cycles have been administered, with a median of 2 cycles (range, 1 to 13 cycles); 10 patients (37%) have received 3 or more cycles of therapy. One of 7 patients treated at dose level 3 of the sequential schedule developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue, weakness, and mucositis. Therefore, the MTD was not reached in the 3 planned dose levels of the sequential schedule. One DLT (grade 3 fatigue) occurred in 6 patients treated at dose level 2 of the concurrent schedule. Most common drug-related non-hematological toxicities of any grade (all CTCAE grades 1 or 2) were nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%). No other non-hematological grade 3 or 4 toxicities were observed. Of the 25 evaluable patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic leukemia-free state (without blood count recovery), and three partial remissions (1 achieved red cell transfusion independency and a second normalization of platelet counts). Seven of these patients remain on study for 2.7 to 13.5+ months. Correlative studies examining histone acetylation and gene promoter methylation in leukemic cells at baseline and after treatment, as well as plasma pharmacokinetic levels for both decitabine and vorinostat are being evaluated. Conclusions: The combination of decitabine and vorinostat is safe, well-tolerated, and has clinical activity in patients with AML. Enrollment is ongoing.

Final results from a phase I trial of ixabepilone in patients with advanced malignancies and lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2039-2039
Author(s):  
C. Aghajanian ◽  
O. O’Connor ◽  
M. Cohen ◽  
R. Peck ◽  
H. Burris
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Phase Ii Studies ◽  
Grade 3

2039 Background: Ixabepilone is the first analog in a new class of antineoplastic agents, the epothilones, which stabilizes microtubules and induces apoptosis. Ixabepilone has shown clinical activity in a broad range of tumors. Methods: This Phase I trial was designed to establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), efficacy, safety, pharmacokinetics and pharmacodynamics of ixabepilone when administered as a 1-hour infusion every 3 weeks to patients with advanced solid tumors or lymphoma. Eligible patients were aged ≥18 years with histologically/cytologically confirmed non-hematologic cancer, or a pathologic diagnosis of relapsed/primary refractory non-Hodgkin’s lymphoma (NHL) or relapsed/primary refractory mantle cell lymphoma, with ≤CTC Grade 1 neuropathy. Ixabepilone doses ranged from 7.5–65 mg/m2. Response was assessed every 6 weeks using RECIST. DLT was defined as Grade 4 neutropenia and/or febrile neutropenia, thrombocytopenia, ≥Grade 3 nausea/vomiting and non-hematologic toxicity, or treatment delay of >2 weeks due to delayed recovery. Results: Of 61 patients (median age 58, range 18–81), 75% had solid tumors; 25% had lymphoma. 98% and 67% of patients had received one or ≥ two prior chemotherapy regimens, respectively. The MTD of ixabepilone as a 1-hour infusion every 3 weeks was established as 50 mg/m2. The most common DLTs were neutropenia, myalgia, arthralgia and stomatitis/pharyngitis. A total of eight patients (13%) achieved a durable objective response. Complete responses were achieved in two patients with primary peritoneal cancer and NHL. A partial response was seen in six patients. The most common Grade 3/4 treatment-related adverse events (only observed at doses ≥40 mg/m2) were sensory neuropathy (13%), fatigue (13%), myalgia (10%), arthralgia (7%), nausea (5%), febrile neutropenia (5%) and neutropenia (5%). Recovery to baseline or ≤Grade 1 neuropathy occurred in some patients. Conclusions: The recommended dose of ixabepilone for the initiation of Phase II studies based on this study is 50 mg/m2 over 1 hour every 3 weeks. Ixabepilone demonstrates promising safety in patients with solid tumors or lymphoma who have failed standard therapy. Encouraging activity was reported in several tumor types. [Table: see text]

X-TRAP: Phase I/II study of capecitabine (X) plus ziv-aflibercept (TRAP) in metastatic colorectal cancer (mCRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
John H. Strickler ◽  
Fatima A. Rangwala ◽  
Christel Rushing ◽  
Donna Niedzwiecki ◽  
Ivy Altomare ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Oral Mucositis ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Clinical Activity ◽  
Combination Methods ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Expansion Cohort

687 Background: Patients (pts) with chemotherapy refractory mCRC have a poor prognosis, with a median survival of approximately 6 months (mos). Ziv-aflibercept is FDA-approved in combination with FOLFIRI for the 2nd line treatment of mCRC, but its tolerability and activity in pts with chemotherapy refractory disease is unknown. We designed a phase I/II study of X+TRAP to define the recommended phase II dose (RPTD), and assess the safety, tolerability, and clinical activity for the combination. Methods: Eligible pts with refractory, advanced solid tumors were enrolled in a 3+3 dose escalation cohort (ESC) to identify the RPTD. Cycle length was 21 days. Radiographic assessment occurred every 3 cycles. X was administered po bid on days 1-14. The dose of X was 850 mg/m2 bid in ESC cohort 1 and 1,000 mg/m2 bid in ESC cohort 2. TRAP was administered on day 1 of each cycle (6 mg/kg IV). Pts with mCRC that had progressed on all standard therapies were then enrolled in a single-arm, phase II expansion cohort (EXP) and treated at the RPTD. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Results: As of 6/19/2015, 55 pts were evaluable for toxicity (13 ESC; 42 EXP) and 47 pts were evaluable efficacy (12 ESC; 35 EXP). In the phase I ESC cohorts, 3 DLTs occurred (1/6 cohort 1; 2/6 cohort 2): GI perforation (1), oral mucositis (1), and fatigue (1). The RPTD was X (850 mg/m2 po bid, days 1-14) and TRAP (6 mg/kg IV, day 1). In the ESC and EXP cohorts, there were no treatment related grade 4/5 adverse events (AEs). The most frequently reported treatment related AEs (grades 2+3; grade 3) were palmar-plantar erythrodysesthesia (36%; 5%), hypertension (29%; 20%), and oral mucositis (18%; 4%). Median follow up in the phase II EXP cohort was 9.3 mos (95% C.I., 6.5–11.1). Median PFS was 4.1 mos (95% C.I., 2.3-4.8). Response assessment in 35 pts (n; %): partial response (PR) (2; 6%); stable disease (SD) (12; 34%); SD > 6 mos (2; 6%). Median OS was 9.3 mos (95% C.I., 6.2–n/a). Conclusions: The combination of X+TRAP demonstrated an acceptable safety profile, with encouraging clinical activity at the RPTD. Recruitment for the phase II EXP cohort is now complete. Clinical trial information: NCT01661972.

AAML 1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A Report from the Children’s Oncology Group.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10003-10003 ◽  
Author(s):  
Todd Michael Cooper ◽  
Michael Absalon ◽  
Todd Allen Alonzo ◽  
Robert B Gerbing ◽  
Kasey Joanne Leger ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Response Rate ◽  
Residual Disease ◽  
Complete Response ◽  
Dose Finding ◽  
Platelet Recovery ◽  
Best Response ◽  
First Relapse ◽  
Grade 3

10003 Background: Effective regimens with favorable toxicity profiles are needed for heavily pre-treated children with relapsed AML. AAML1421 is a Phase I/II study of CPX-351, a liposomal preparation of cytarabine and daunorubicin demonstrating efficacy in adults. AAML1421 sought to determine the recommended Phase 2 Dose (RPD2) of CPX-351 and the response rate (complete response (CR) + complete response without platelet recovery (CRp)) after up to 2 cycles of therapy. Methods: Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding, and those in first relapse were eligible for efficacy. A modified rolling six design was used for dose-limiting toxicity (DLT) assessment which occurred in Cycle 1. Dose level 1 (DL1) was 135 units/m2 on days 1, 3, and 5 with a single dose de-escalation to 100 units/m2 if DL1 was intolerable. The Efficacy Phase used a Simon-two stage design. The response rate was determined after up to 2 cycles of therapy (Cycle 1: CPX-351; Cycle 2: FLAG). The Overall Response Rate (ORR) was defined as CR+CRp+CRi (CRi = CR with incomplete hematologic recovery). Results: Thirty-eight patients (pts) enrolled: 6 in dose-finding and 32 in the efficacy phase. DLT occurred in 1/6 patients and was a grade 3 decrease in ejection fraction(EF). This was the only Grade 3 cardiac toxicity. Therefore, 135 units/m2 on days 1, 3, 5 was the RP2D. All dose finding pts were eligible for efficacy determination. One pt in the efficacy phase was unevaluable. The most common ≥ Grade 3 toxicities in Cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 CR (54%), 5 CRp (14%), and 5 CRi (14%). Seventy percent achieved best response after cycle 1. Twenty-one of 25 patients with CR/CRp had no detectable residual disease (RD) (84%) by flow cytometry. HSCT was used as consolidation in 23/29 responders (79%); 18 of 23 (78%) had no detectable RD prior to HSCT. Conclusions: The RP2D of CPX-351 is 135 units/m2/dose on days 1, 3, 5. CPX-351 was well tolerated and protocol therapy was effective with CR+CRp rates of 68.3% (90% CI 52.9% to 78.0%) and ORR (CR+CRp+CRi) of 81.1% (90% CI 67.4% to 88.8%). AAML1421 response rates are superior to any published North American cooperative group clinical trial for children with AML in first relapse. Clinical trial information: NCT02642965.

Phase I trial evaluating genetically modified autologous T cells (ACTengine IMA201) expressing a T-cell receptor recognizing a cancer/germline antigen in patients with squamous NSCLC or HNSCC.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS78-TPS78 ◽  
Author(s):  
George R. Blumenschein ◽  
Agathe Bourgogne ◽  
Carsten Reinhardt ◽  
Hong Ma ◽  
Steffen Walter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
T Cell Receptor ◽  
Phase I Trial ◽  
Cell Cancer ◽  
Cell Receptor ◽  
Clinical Activity ◽  
Human Dose ◽  
Cancer Germline

TPS78 Background: Adoptive cellular therapy (ACT) has dramatically changed the landscape of immunotherapy. T-cell receptor (TCR) engineered ACT approach has contributed to success in solid tumors. ACTengine IMA201 is a product based on autologous T cells engineered to express a naturally occurring TCR specific to a cancer-germline peptide. The target peptide has been characterized in depth by Immatics’ proprietary antigen discovery platform, XPRESIDENT showing exceptional specificity, copy number and expression homogeneity. XPRESIDENT has applied two independent methodologies to confirm the selectivity of tumor target: i) ultra-sensitive quantitative immunopeptidome analyses by mass spectrometry and ii) quantitative mRNA expression analyses by RNASeq. Immatics´ TCR discovery platform is optimized to identify TCRs with low micromolar affinity, specific recognition of tumor cell lines and lack of recognition of healthy normal cells. Methods: This study is an open-label first-in-human dose-escalating phase I trial investigating safety, tolerability and clinical activity in end-stage solid tumor patients. Key eligibility criteria include: recurrent or refractory squamous non-small cell lung cancer or head and neck squamous cell cancer, HLA-A*02:01 phenotype, qPCR biomarker positive from a tumor biopsy, prior established lines of therapy, RECIST v1.1 measurable lesions and ECOG score 0 or 1. At baseline, patients will undergo leukapheresis to collect mononuclear cells (PBMC). The activated PBMC will be transduced with a lentiviral vector for manufacturing of IMA201. IMA201 is infused after a pre-conditioning (lymphodepletion) followed by LD-IL2. The primary objective is to assess safety and to identify the maximum tolerated dose. Secondary endpoints include overall response rate (RECIST and irRC), PFS and OS. The translational objectives include: i) the persistence and functionality of IMA201 in vivo, ii) correlative biomarkers for clinical success, and iii) target expression levels in the tumor. Enrollment to the study is currently ongoing. Clinical trial information: NCT03247309 .

Phase Ib trial of ALT-803, an IL-15 superagonist, plus Bacillus Calmette Guerin (BCG) for the treatment of patients with BCG-naïve non-muscle-invasive bladder cancer (NMIBC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 470-470 ◽  
Author(s):  
Charles Joel Rosser ◽  
Jeffrey Nix ◽  
Liza Hernandez ◽  
Peter R. Rhode ◽  
Hing C. Wong
Keyword(s):  
Clinical Trial ◽  
Response Assessment ◽  
Complete Response ◽  
Urinary Cytology ◽  
Induction Phase ◽  
Phase Ib ◽  
Risk Patients ◽  
Grade 3 ◽  
Muscle Invasive

470 Background: Novel agents are necessary to treat NMIBC to avoid recurrence and progression. This phase Ib clinical trial evaluated the safety and toleraibility of ALT-803, an IL-15 superagonist, plus BCG in patients with BCG-naïve NMIBC. Methods: This is a Phase Ib trial using the 3+3 design to evaluate intravesical ALT-803 plus BCG 50 mg in BCG-naïve NMIBC patients, who would normally be eligible for intravesical BCG alone. The initial dose of ALT-803 was 100 μg/instillation with 2 dose-escalations allowed (200 μg/instillation and 400 μg/instillation) if dose limiting toxicities (DLTs) were not evident. Patients received intravesical ALT-803 in conjunction with BCG weekly for 6 consecutive weeks (Induction Phase). Patients then had routine follow-up with cystoscopy and voided urinary cytology (VUC) every 3 months for 2 years equating to confirmatory response assessment. Negative cystoscopy, VUC and/or biopsy yielded a complete response (CR). When appropriate for high-risk patients, physicians and patients were encouraged to receive maintenance BCG alone as per common practice patterns. Results: No patient in 100 μg/instillation of ALT-803/BCG and 200 μg/instillation of ALT-803/BCG reported an AE. One patient in 400 μg/instillation/BCG cohort developed a urinary tract infection requiring delay of intravesical treatment by 1 week. No grade 3/4 toxicities were noted. All patients have completed therapy without DLTs. To date, 4 patients have 12 month follow-up and are CR. The remaining 5 patients have no evidence of disease. However, follow-ups are currently approximately 3 months. Corollary immune studies are still pending. Conclusions: Intravesical ALT-803 plus BCG was safe and tolerable in patients with BCG-naive NMIBC. Further evaluation in expansion cohorts in a phase II trial is currently underway. Clinical trial information: NCT02138734.

Phase I and Pharmacokinetic Study of Lapatinib in Combination With Capecitabine in Patients With Advanced Solid Malignancies

2007 ◽  
Vol 25 (24) ◽  
pp. 3753-3758 ◽  
Author(s):  
Quincy S.C. Chu ◽  
Garry Schwartz ◽  
Johann de Bono ◽  
Deborah A. Smith ◽  
Kevin M. Koch ◽  
...  
Keyword(s):  
Phase I ◽  
Area Under The Curve ◽  
Pharmacokinetic Interaction ◽  
Complete Response ◽  
Clinical Activity ◽  
Once Daily ◽  
Common Drug ◽  
Solid Malignancies ◽  
Previously Treated ◽  
Grade 3

Purpose This phase I trial ( EGF10005 ) assessed the safety, optimally tolerated regimen (OTR), and pharmacokinetics of lapatinib and capecitabine in combination in patients with advanced solid malignancies. Patients and Methods Patients with previously treated, advanced solid malignancies were eligible. Cohorts of at least three patients each received once-daily oral lapatinib (continuous) and capecitabine (twice daily for 14 days every 21 days). Doses of lapatinib and capecitabine were escalated based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. Additional patients were treated at the OTR dose level to further evaluate safety and for pharmacokinetic analyses. Results Forty-five patients were treated in the study. The OTR was determined to be lapatinib 1,250 mg/d plus capecitabine 2,000 mg/m2/d. The majority of drug-related adverse events were grade 1 to grade 2 in severity, with few grade 3 and no grade 4 toxicities. The most common drug-related toxicities (> 15% of patients) were diarrhea, nausea, rash, palmar-plantar erythrodysesthesia, mucositis, vomiting, and stomatitis. There were four confirmed responses (one complete response and three partial responses). The pharmacokinetics (area under the curve and maximum concentration) of lapatinib, capecitabine and its metabolites, fluorouracil, and α-fluoro-β-alanine, were not meaningfully altered by coadministration. Conclusion Lapatinib and capecitabine administered on a 3-week schedule were well tolerated, and no pharmacokinetic interaction was observed. Clinical activity was observed in patients with previously treated, advanced solid malignancies.

Phase I Trial of Intravesical Gemcitabine in Bacillus Calmette-Guérin–Refractory Transitional-Cell Carcinoma of the Bladder

2002 ◽  
Vol 20 (15) ◽  
pp. 3193-3198 ◽  
Author(s):  
Guido Dalbagni ◽  
Paul Russo ◽  
Joel Sheinfeld ◽  
Madhu Mazumdar ◽  
William Tong ◽  
...  
Keyword(s):  
Phase I ◽  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Transitional Cell ◽  
Response Assessment ◽  
Complete Response ◽  
Bacillus Calmette Guerin ◽  
Mixed Response ◽  
Bcg Therapy ◽  
Grade 3

PURPOSE: The aim of this phase I study was to determine the safety and toxicity profile of gemcitabine administered as an intravesical agent in patients with transitional-cell carcinoma (TCC) of the bladder. PATIENTS AND METHODS: Patients with superficial bladder cancer refractory to intravesical bacillus Calmette-Guérin (BCG) therapy and refusing a cystectomy were considered eligible for the trial. Gemcitabine was given in the bladder for 1 hour twice weekly in 100 mL sodium chloride for a total of six treatments. After a 1-week break, a second course of six treatments over 3 weeks was given, followed by response assessment. Four dose levels were explored: 500 mg, 1,000 mg, 1,500 mg, and 2,000 mg. RESULTS: Eighteen patients completed therapy: three at 500 mg, six at 1,000 mg, three at 1,500 mg, and six at 2,000 mg. No grade 3 or 4 toxicity was observed at 500 mg. At 1,000 mg, three patients developed hematuria and one had a skin reaction resembling grade 3 hand-foot syndrome. Three patients at 1,500 mg had no grade 3 or 4 toxicity. Of six patients at 2,000 mg, one had grade 3 thrombocytopenia and neutropenia without infection. Seven patients had a complete response (negative cytology and posttreatment biopsy), and four patients had a mixed response (negative bladder biopsy but positive cytology). CONCLUSION: Gemcitabine has substantial activity as an intravesical agent in BCG-refractory TCC and warrants further investigation. Therapy given twice weekly was associated with minimal bladder irritation and tolerable myelosuppression. The recommended phase II dose for twice-weekly therapy is 2,000 mg.

Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL): Results of the Phase Ib GAUDI Study (BO21000)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3686-3686 ◽  
Author(s):  
Martin JS Dyer ◽  
Andrew Grigg ◽  
Marcos González ◽  
Martin Dreyling ◽  
Simon A. Rule ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Assessment ◽  
Complete Response ◽  
Type Ii ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 3686 GA101 is a glycoengineered, humanized type II anti-CD20 monoclonal antibody (mAb) anticipated to have superior B-cell-depleting activity to rituximab in vivo on the basis of its enhanced FcR binding and because of the direct cell death induced by type II CD20 mAbs. GA101 has shown significant single-agent activity in Phase I and II studies in patients with FL, and activity in combination with CHOP and fludarabine plus cyclophosphamide in patients with resistant/refractory FL in the first part of this Phase I trial (Radford et al. ASH 2011; abstract 270). This report describes the safety, toxicity, and efficacy of remission induction of GA101 in combination with CHOP or bendamustine in 81 patients aged > 18 years with treatment-naïve CD20+ grade 1–3b FL with at least one measurable lesion (longest diameter > 1.5 cm by CT scan). All patients received a flat dose of GA101 (1,000 mg on Days 1 and 8 of Cycle 1 and Day 1 of subsequent cycles) combined with either 6–8 cycles of CHOP (every 3 weeks) or 4–6 cycles of bendamustine (90 mg/m2Days 1 and 2 every 4 weeks) on a per center choice basis. Patients achieving complete response (CR) or partial response (PR) were eligible to receive GA101 maintenance therapy (1,000 mg) every 3 months for 2 years or until progression. The primary objective was safety, and secondary objectives included overall response rate (ORR), CR rate, and pharmacokinetics. Response was assessed at the end of induction using International Working Group response criteria; unconfirmed CRs were classified as PRs. 40 patients received G-CHOP and 41 G-bendamustine. Baseline characteristics were similar for both groups: median age 53.5 and 57 years; bone marrow involvement 53% and 49%; bulky disease (≥ 7 cm) 45% and 41%; Median time from diagnosis was only 1.20 months for both groups, high-risk FLIPI status (3–5) 45% and 46%, and intermediate risk (FLIPI 2) 38% and 34%. 38 G-CHOP and 37 G-bendamustine patients completed all cycles of planned induction therapy. Three patients withdrew without any response assessment. In the G-CHOP arm, one withdrawal was due to a GA101-associated infusion-related reaction [IRR] after Cycle 1 and another patient was found to be ineligible and withdrawn after Cycle 1. In the G-bendamustine arm one patient withdrew consent after Cycle 2. Three other patients were withdrawn after interim response assessment, none for safety reasons (insufficient response in the G-bendamustine arm and administrative reasons for two in the G-CHOP arm). The most frequent adverse events were IRRs (all grades: 58% G-CHOP; 59% G-bendamustine; grade 3/4: 5% G-CHOP; 10% G-bendamustine). No Grade 3/4 IRRs occurred after cycle 3. Grade 3/4 neutropenia was reported in 43% of patients in the G-CHOP arm and 29% of patients in the G-bendamustine arm during induction, resulting in delayed delivery of 7.0% and 4.8% of chemotherapy cycles. All delays but one were no longer than 2 weeks. Grade 3/4 infections occurred in 23% of patients receiving G-CHOP and 10% of patients receiving G-bendamustine. Approximately half of these were neutropenic infections or sepsis and all resolved with appropriate management. ORR at the end of the induction period was 95% (38/40) in the G-CHOP arm (CR rate 35%) and 92.7% (38/41) in the G-bendamustine arm (CR rate 39%) (Table). Serum GA101 concentrations increased during the induction period and were similar for both regimens. Mean Cmax was 300–600 μg/mL and Cmin100–300 μg/mL. Following the final administration, a decline in GA101 serum concentration was seen that was similar for the two treatment combinations. In conclusion, efficacy and safety data for GA101 combined with CHOP and bendamustine are encouraging for first-line treatment of patients with FL. Based on these promising results GA101 is now being studied in combination with various chemotherapy regimens in a randomized Phase III study against the standard of care, rituximab-based immunochemotherapy. Patients, n (%) G-CHOP (n = 40) G-bendamustine (n = 41) Efficacy     Overall response 38 (95.0) 38 (92.7)     Complete response* 14 (35.0) 16 (39.0)     Partial response 24 (60.0) 22 (53.7)     Stable disease 0 1 (2.4)     Progressive disease 0 1 (2.4)     Not assessed 2 (5.0) 1 (2.4) Safety     Grade 3/4 IRRs 2 (5.0) 4 (9.8)     Grade 3/4 neutropenia 17 (43) 12 (29)     Grade 3/4 infections 9 (23) 4 (10) * CRu were classified as PR Disclosures: Dyer: Roche: Consultancy, Research Funding. Off Label Use: Obinutuzumab (GA101) in Combination with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) or Bendamustine in Patients with Previously Untreated Follicular Lymphoma (FL). Grigg:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Support of (other) clinical trials and Scientific Advisory Boards Other. Rule:Roche: Consultancy, Research Funding. Lei:Roche: Employment. Wassner-Fritsch:Roche: Employment. Wenger:Roche: Employment. Marlton:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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