Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
Gregory Lawrence Beatty ◽  
Peter J. O'Dwyer ◽  
Jason Clark ◽  
Jack G Shi ◽  
Robert Charles Newton ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Adverse Events ◽  
Immune Responses ◽  
Dose Escalation Study ◽  
Advanced Malignancies ◽  
Common Grade ◽  
Ido1 Expression ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Dependent

3025 Background: INCB024360 is a potent, selective inhibitor of IDO1. As the catabolism of tryptophan (Trp) to kynurenine (Kyn) by IDO1 inhibits immune responses and IDO1 expression is elevated in many human cancers, IDO1 inhibition may potentiate effective antitumor immune responses. Methods: This dose-escalation study in adult pts with advanced malignancies used a 3+3 design to determine MTD, toxicity, PK, PD, and tumor response rate. Daily doses of INCB024360 were evaluated in 28-day cycles in 8 cohorts (50 mg once daily; 50 mg, 100 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg BID). Treatment continued until disease progression or unacceptable toxicity. PK and PD samples were drawn on days 1 and 15. Results: 52 pts have been treated. Tumor types included colorectal (56%), melanoma (12%), and other (33%). The most common adverse events (≥20%) were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. The most common grade 3 or 4 adverse events were abdominal pain, hypokalemia, and fatigue (9.6% each). One DLT each was observed at 300 mg BID (grade 3 radiation pneumonitis) and 400 mg BID (grade 3 fatigue); no DLTs were observed in the 18 pts treated with 600 mg or 700 mg BID. There were no objective responses. At 56 days, stable disease was seen in 15 patients and lasted ≥112 days in 7 patients. Significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected at all doses and in all pts. Maximal effects were observed at doses ≥300 mg BID. With repeat dosing, 700 mg BID provided an average plasma concentration ~5-fold the projected IC90. Overall, doses ≥300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. Conclusions: INCB024360 was generally well tolerated at doses of up to 700 mg BID and there appears to be no correlation of dose with toxicity. Doses ≥300 mg BID were capable of >90% inhibition of IDO1 activity and found to effectively normalize plasma Kyn levels. The recommended dose as monotherapy is 600 mg BID. Clinical trial information: NCT01195311.

Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase I dose-escalation study in patients with FGFR genomically activated advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2500-2500 ◽  
Author(s):  
Martin Henner Voss ◽  
Cinta Hierro ◽  
Rebecca Suk Heist ◽  
James M. Cleary ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Fibonacci Sequence ◽  
Genetic Alterations ◽  
Fibroblast Growth Factor Receptors ◽  
Dose Escalation Study ◽  
Cutaneous Toxicity ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Dependent ◽  
Gene Alterations

2500 Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumor malignancies. Debio 1347 is an orally available, highly selective panFGFR inhibitor with potent antitumor effect in preclinical models bearing FGFR1-3 genetic alterations. Methods: Patients harboring defined FGFR 1, 2 or 3 alterations received escalating doses of Debio 1347 starting from 10 mg once daily. Dose escalation followed a 3+3+3 algorithm based on a modified Fibonacci sequence. The MTD was defined as the level where ≥ 3/9 patients suffer a DLT. Pharmacokinetics (PK) and pharmacodynamic were serially evaluated in blood, skin and/or tumor tissue. Results: Fifty-six patients were enrolled, including patients with mutations (n = 17), amplifications (n = 28) and fusions (n = 11). The dose was escalated up to 150 mg over 8 cohorts. DLTs were experienced by 4/56 patients, including G2 intolerable dry mouth + eyes at 60 mg, G3 hypercalcemia + hyperamylasemia at 80 mg, and G3 bilirubin increase at 110 mg. At data cut-off, the most common treatment-emergent adverse events (TEAE) were hyperphosphatemia (73%), fatigue (41%), diarrhea (39%), nausea (37%), and inappetence (32%). Fifteen patients (27%) experienced a grade ≥ 3 related TEAE. Twenty-five patients (47%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. An MTD has not been reached. PK appeared overall linear, with a half-life of 14 hours; hyperphosphatemia was dose-dependent. Among the 54 response-evaluable patients, 4 confirmed and 1 unconfirmed partial responses were observed in patients with cholangiocarcinoma (FGFR2 mutant), uterine (FGFR2 and FGFR1 amplified), colon (FGFR2 fusion), and urothelial cancer (FGFR3 fusion); an additional 10 patients had target regression < 30%. Conclusions: Debio 1347 had a tolerable and manageable safety profile. Encouraging antitumor activity was seen in several tumor types, mainly in patients with FGFR2 or 3 gene alterations, including fusion events, treated at 80 mg and 110 mg daily. Efficacy will be further explored in disease-specific and molecularly defined expansion cohorts. Clinical trial information: NCT1948297.

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

Gemcitabine Plus Nab-Paclitaxel as Second-Line Chemotherapy following FOLFIRINOX in Patients with Unresectable Pancreatic Cancer: A Single-Institution, Retrospective Analysis

Chemotherapy ◽  
2021 ◽  
pp. 1-7
Author(s):  
Kotone Hayuka ◽  
Hiroyuki Okuyama ◽  
Akitsu Murakami ◽  
Yoshihiro Okita ◽  
Takamasa Nishiuchi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adverse Events ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Unresectable Pancreatic Cancer ◽  
Line Treatment ◽  
Second Line ◽  
Free Survival ◽  
Common Grade ◽  
Grade 3

<b><i>Introduction:</i></b> Patients with advanced pancreatic cancer have a poor prognosis. FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) have been established as first-line treatment, but they have not been confirmed as second-line treatment after FFX. The aim of this study was to evaluate the safety and efficacy of GnP as second-line therapy after FFX in patients with unresectable pancreatic cancer. <b><i>Methods:</i></b> Twenty-five patients with unresectable pancreatic cancer were enrolled. The patients were treated with GnP after FFX between September 2015 and September 2019. Tumor response, progression-free survival (PFS), overall survival (OS), and incidence of adverse events were evaluated. <b><i>Results:</i></b> The response rate, disease control rate, median PFS, and median OS were 12%, 96%, 5.3 months, and 15.6 months, respectively. The common grade 3 or 4 adverse events were neutropenia (76%) and anemia (16%). <b><i>Conclusions:</i></b> GnP after FOLFIRINOX is expected to be one of the second-line recommendations for patients with unresectable pancreatic cancer.

Phase I INSIGHT platform trial: Advanced safety and efficacy data from stratum D evaluating feasibility and safety of eftilagimod alpha (soluble LAG-3 protein) combined with avelumab in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2518-2518
Author(s):  
Thorsten Oliver Goetze ◽  
Daniel Wilhelm Mueller ◽  
Mohammad-Reza Rafiyan ◽  
Dragan Kiselicki ◽  
Timursah Habibzade ◽  
...  
Keyword(s):  
Adverse Events ◽  
Renal Insufficiency ◽  
Diffuse Myocardial Fibrosis ◽  
Pleural Mesothelioma ◽  
Advanced Solid Tumors ◽  
Clinical Progression ◽  
Grade 5 ◽  
Common Grade ◽  
Acute Renal Insufficiency ◽  
Grade 3

2518 Background: Stratum D of the INSIGHT platform trial evaluates s.c. eftilagimod alpha (efti, IMP321) combined with avelumab in advanced solid tumors. Efti is an MHC class II agonist which activates antigen-presenting cells followed by CD8 T-cell activation. Combination with PD-1/PD-L1 blockade aims at enhanced efficacy. Methods: This IIT platform trial consists of 5 strata: intratumoral (A) or intraperitoneal efti (B); s.c. efti with SOC (C) or with PD-L1 inhibition (D). Strat E is currently under development and starts soon with a new efti combination. This abstract focuses on preliminary data of Strat D. Patients (pts) received 800mg avelumab i.v. q2w along with s.c. efti: 6mg in cohort 1 (coh 1, 6 pts), 30mg in cohort 2 (coh 2, 6 pts). Primary endpoint: safety. Results: Recruitment has been completed with 12 pts (coh 1: gastric, gallbladder, colon cancer, pleural mesothelioma; coh 2: gastric, gastroesophageal, anal, rectum, cervix uteri). No dose limiting toxicities (DLTs) occurred. 10 serious adverse events (SAEs) were reported, none of them considered causally related (4 in 3 pts of coh 1 [1 acute renal insufficiency grade 5 in 1 pt, 2 preileus grade 3 in 1 pt, hearing impaired grade 4 in 1 pt] and 6 in 4 pts of coh 2 [1 anal hemorrhage and 1 gallbladder obstruction in 1 pt, 1 eye pain and 1 surgery to replace the feeding tube in 1 pt, each grade 3, 1 skin infection grade 2, 1 diffuse myocardial fibrosis grade 5]. 1 AE of special interest (AESI) possibly related with avelumab (sarcoidosis grade 1) occurred in coh 1. 2 pts completed max treatment duration with 24 cycles. In coh 1, 47 adverse events (AEs; grade 1-2, 29; grade 3, 14; grade 4, 3; grade 5, 1) occurred in 5 pts. Most common grade 1-2 AEs were nausea, pain in 33%, 33% of the pts. Most common grade 3 AEs were ileus, vomiting in 33%, 33% of the pts. 2 AEs grade 4 (hearing impaired, sepsis) and 1 AE grade 5 (acute renal insufficiency) were reported. All AEs grade 3-5 were considered causally unrelated. In coh 2, 51 adverse events (AEs; grade 1-2, 29; grade 3, 19; grade 4, 2; grade 5, 1) occurred in 5 pts. The most common grade 1-2 AE was hypothyroidism in 33% of the pts. 1 AE grade 5 (diffuse myocardial fibrosis) was reported. Only 1 AE grade 3-5 was considered causally related (urinary tract infection grade 3 related with avelumab). 5 pts showed partial response as best response (2 coh 1: colon, pleural mesothelioma; 3 coh 2: gastric, anal, cervical), 1 stable disease with clinical progression (coh 2) (all but one of these pts still alive), 5 disease progressions acc. to RECIST 1.1 (3 coh 1, 2 coh 2), 1 clinical progression (coh 1). Signals of activity were also observed in pre-treated MSS/PD-L1low pts. Conclusions: Combined treatment with avelumab 800mg and efti 6mg (coh 1) or 30 mg efti (coh 2) seems feasible and safe. No unexpected AEs occurred. Signals of efficacy with CPI combination were seen (DCR 50%). Clinical trial information: NCT03252938.

scholarly journals Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

2020 ◽  
Vol 38 (6) ◽  
pp. 1836-1845
Author(s):  
Shunsuke Kondo ◽  
Masaomi Tajimi ◽  
Tomohiko Funai ◽  
Koichi Inoue ◽  
Hiroya Asou ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Japanese Patients ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Dual Inhibitor ◽  
Advanced Malignancies ◽  
Grade 3

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

scholarly journals Rheumatological Adverse Events Following Immunotherapy for Cancer

Medicina ◽  
2022 ◽  
Vol 58 (1) ◽  
pp. 94
Author(s):  
Ioana Cretu ◽  
Bogdan Cretu ◽  
Catalin Cirstoiu ◽  
Adrian Cursaru ◽  
Mihaela Milicescu ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Adverse Reactions ◽  
Cancer Treatments ◽  
Treatment Conditions ◽  
Clinical Presentations ◽  
Rheumatic Manifestations ◽  
Grade 3 ◽  
Dose Dependent ◽  
Rheumatological Manifestations

Background and Objectives: The occurrence of rheumatological side effects in a patient after receiving immunotherapy for cancer is becoming increasingly common. Oncologists often fail to diagnose and refer affected patients to rheumatologists. This paper presents the various rheumatological adverse events that occur after immunotherapy in patients as well as their treatment and evolution. Materials and Methods: A total of 36 patients were monitored between November 2018 and March 2020. The oncologist monitoring the immunotherapy-treated patients identified the occurrence of musculoskeletal side effects. The grading of toxicities was performed by both the oncologist and the rheumatologist using common terminology criteria for adverse events (CTCAE). Rheumatological treatment was administered, and for some patients, immunotherapy was discontinued. Results: The clinical presentations of the patients varied. Mild side effects (grade 1–2) were reported in a higher proportion than severe side effects (grade 3–5). Therefore, thirty-one patients had mild-to-moderate side effects, and five patients had severe side effects. Adverse reactions occurred, on average, 10 weeks after the initiation of immunotherapy; this indicated that the severity of the toxicity was dose dependent. Patients were treated with NSAIDs or prednisone, depending on the severity of the side effects, and for patients with severe manifestations, immunotherapy was discontinued. The remission of rheumatic manifestations varied depending on the grade of the manifestations. Conclusions: The clinical, biological, and ultrasound presentations of the patients with adverse events followed by cancer treatments differed from classic rheumatological manifestations. Thorough examinations of these patients by both oncologists and rheumatologists are needed in order to correctly diagnose and treat rheumatological adverse events. Multiple studies that include a larger number of participants are needed in order to better understand the pathogenesis and clinical evolution of these patients under different treatment conditions.

Biweekly Raltitrexed in Combination with Irinotecan (RIR) as Second-Line Therapy for Patients with Metastatic Colorectal Cancer: A Non-Randomized, Open-Label Phase II Trial.

2020 ◽  
Author(s):  
Ke Cheng ◽  
Yu-Wen Zhou ◽  
Ye Chen ◽  
Zhi-Ping Li ◽  
Meng Qiu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Overall Response Rate ◽  
Progression Free Survival ◽  
Second Line ◽  
Open Label ◽  
Second Line Therapy ◽  
Free Survival ◽  
Common Grade ◽  
Open Label Phase ◽  
Grade 3

Abstract Background Irinotecan-based doublet chemotherapy strategy was standard second-line backbone treatment for patients with oxaliplatin‑refractory metastatic colorectal cancer(mCRC). The aim of this study was to evaluate tolerability and efficacy of raltitrexed combined with irinotecan biweekly administered as the second-line therapy for mCRC patients.Methods The study was a single-center, non-randomized, open-label phase II trial. Patients with mCRC after failure with first-line treatment of oxaliplatin and fluoropyrimidine or its derivatives were enrolled. Irinotecan (180 mg/m2) and raltitrexed (2.5 mg/m2) were given intravenously on day 1. Cycles were repeated every 2 weeks. The primary endpoint was progression-free survival, and the secondary endpoints included overall response rate, disease control rate, overall survival and treatment related adverse events. Results Between December 2012 and October 2016, 35 patients were enrolled. 33 and 35 patients were assessed for response and safety, respectively. The overall response rate (ORR) was 8.6 %, and the disease control rate (DCR) was 71.4%. The median progression-free survival (PFS) was 4.5 months (95% CI 3.8–5.2). The median overall survival was 12.0 months (95% CI 8.5–15.5). Four patients received conversion therapy to no evidence of disease (NED), and 2 patients were still alive with beyond 24 months survival. The most common grade 3/4 hematological adverse events were leukopenia (8.6%), neutropenia (5.7%). The most common grade 3/4 nonhematological adverse events were anorexia (14.3%), vomiting (14.3%), nausea (11.4%) and fatigue (8.6%). Two patients discontinued the protocol treatment because of treatment-related gastrointestinal adverse events. No one died from treatment-related events. The incidence and severity of toxicity was irrelevant to UGT1A1 status.Conclusions The combination of irinotecan with raltitrexed is an active, convenient and acceptable toxic regimen for second-line treatment for mCRC patients, which needs further study as a chemotherapy backbone to be combined with targeted agents in mCRC.Trial registration No. ChiCTR-ONC-12002767. The study was registered with the Chinese Clinical Trial Registry at 29 Octorber 2012, http://www.chictr.org.cn/index.aspx.

scholarly journals A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti–PD-1 antibody, in patients with advanced solid tumors

2020 ◽  
Vol 8 (1) ◽  
pp. e000530 ◽  
Author(s):  
Aung Naing ◽  
Justin F Gainor ◽  
Hans Gelderblom ◽  
Patrick M Forde ◽  
Marcus O Butler ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Wide Range ◽  
Tumor Types ◽  
Tumor Biopsies

BackgroundSpartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors.MethodsIn the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W).ResultsPatients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit.ConclusionsSpartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types.Trial registration numberNCT02404441.

Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

2008 ◽  
Vol 26 (30) ◽  
pp. 4952-4957 ◽  
Author(s):  
Peter H. Wiernik ◽  
Izidore S. Lossos ◽  
Joseph M. Tuscano ◽  
Glen Justice ◽  
Julie M. Vose ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Large B Cell

PurposeThe major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL.Patients and MethodsPatients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety.ResultsForty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%).ConclusionOral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.

A phase II study of capecitabine and oxaliplatin (CAPOX) in metastatic adenocarcinoma of the small bowel (SBA) or ampulla of Vater

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14025-14025
Author(s):  
M. J. Overman ◽  
S. Chedid ◽  
J. Morris ◽  
S. Waldrum ◽  
R. A. Wolff
Keyword(s):  
Small Bowel ◽  
Performance Status ◽  
Complete Response ◽  
Ampulla Of Vater ◽  
Ecog Performance Status ◽  
Ampullary Adenocarcinoma ◽  
Highly Active ◽  
Common Grade ◽  
Grade 3 ◽  
Tumor Types

14025 Background: Metastatic SBA and ampullary adenocarcinoma (AAC) are incurable, aggressive malignancies. Limited data exists regarding the role of systemic chemotherapy in these diseases. Given the marked activity of CAPOX in other cancers of the gastrointestinal tract, we have investigated the activity of this combination in these two tumor types. Methods: Patients (pts) with either metastatic or unresectable SBA and AAC who had adequate organ function, ECOG performance status (PS) ≤2 and measurable disease per modified RECIST criteria were enrolled. Prior use of 5-FU or capecitabine as adjuvant therapy, neoadjuvant therapy, or with radiation was allowed. CAPOX was administered as a 21 day cycle with oxaliplatin 130mg/m2 IV on day 1 and capecitabine 750mg/m2 PO BID days 1–14. Up to 30 pts will be enrolled. The primary endpoint is overall response rate (ORR). Results: Eleven pts have been enrolled from 11/04 to 12/05 (6 with AAC and 5 with SBA). Ten pts have received ≥2 cycles and are evaluable for response. All pts had metastatic disease and none had received prior chemotherapy. Patient (pt) characteristics: median age 59 (49–76); M/F (4/7); 91% PS 0–1. Grade 3/4 toxicities included fatigue (5), neuropathy (1), anorexia (1), thrombocytopenia (1), hypokalemia (1), hyponatremia (1), and musculoskeletal (1). Common grade 1/2 toxicities included neuropathy (8), nausea (8), diarrhea (6), and fatigue (5). Four pts required dose reduction and 1 pt discontinued due to toxicity (grade 3 fatigue). Six pts, 3 AAC and 3 SBA, responded with an ORR of 60% (95% CI 31 to 83%). Five responses have been confirmed and 1 AAC pt obtained a complete response after 5 cycles of treatment. Median time to progression was 6.8m (95% CI 4.4 to 9.3+m). Conclusions: The combination of CAPOX is both well-tolerated and highly active. The ORR of 60% is one of the highest yet reported in the literature for the treatment of adenocarcinoma of the small bowel and ampulla of Vater. Enrollment continues on this trial. (Supported by a research grant from Sanofi-Aventis). [Table: see text]

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