Assessment of safety with abbreviated, weight-based bevacizumab infusions in a variety of solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19674-19674
Author(s):  
J. W. Hart ◽  
J. R. Murillo ◽  
M. S. Oholendt ◽  
H. A. Preti
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Central Nervous System Involvement ◽  
Minimal Risk ◽  
Phase I Clinical Trials ◽  
Multiple Tumor ◽  
Humanized Monoclonal Antibody ◽  
Number Of Patients ◽  
Infusion Schedule ◽  
Tumor Types

19674 Background: Bevacizumab (BEV), a humanized monoclonal antibody that neutralizes vascular endothelial growth factor, has shown improved responses in patients with colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) while displaying activity in a variety of other solid tumors. Phase I clinical trials with BEV utilized standard 90- 60-, and 30-minute infusions for 1st, 2nd, and subsequent infusions, as tolerated; initial doses reported less than 3% incidence of infusion-related adverse events (AEs), with 0.2% grade III/IV reactions. Recommended infusion rates for BEV remain unchanged despite the minimal risk of infusion-related AEs. Saltz and colleagues recently reported novel data supporting the safety and tolerability of abbreviated BEV infusions in CRC patients within a single institution. Our objective was to replicate previously reported safety profiles while utilizing abbreviated infusions of BEV in multiple tumor types. Methods: An internal retrospective analysis revealing minimal infusion AEs with standard infusions facilitated this current study. BEV- naïve and previously-treated patients were consented for the study utilizing the following weight-based infusion times: 5, 10, and 15 mg/kg doses over 10, 20, or 30 minutes, respectively, for all doses. Patients were assessed throughout and immediately following the infusion for any infusion-related AE. Results: A variety of tumor types are represented in 26 enrolled patients including CRC, NSCLC, breast, ovarian, pancreatic, and brain. Central nervous system involvement accounted for 35% of patients [primary brain (23%) and metastatic disease (12%)]. A considerable number of patients (19%) were treated with single-agent BEV. Nine BEV-naïve patients were initiated on abbreviated infusions, while 16 were converted from the standard infusion schedule. Seventy-seven total doses utilizing the abbreviated infusions failed to produce infusion-related AEs. Conclusion: These results support previous data affirming the safety and tolerability of abbreviated BEV infusions in CRC patients, while also reporting promising safety of abbreviated infusions in a variety of additionally unreported solid tumors types. No significant financial relationships to disclose.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

A phase 1 trial of FID-007, a novel nanoparticle paclitaxel formulation, in patients with solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3021-3021
Author(s):  
Jacob Stephen Thomas ◽  
Diane Habib ◽  
Diana L. Hanna ◽  
Irene Kang ◽  
Syma Iqbal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Topical Therapy ◽  
Maculopapular Rash ◽  
Primary Objective ◽  
Multiple Tumor ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Proportional

3021 Background: FID-007 (FID) consists of paclitaxel encapsulated in a polyethyloxazoline (PEOX) polymer excipient designed to enhance PK, biodistribution, and tolerability. In addition to allowing the drug to remain in solution until it can enter a cancer cell, the PEOX nanoparticle preferentially delivers paclitaxel to the tumor through the leaky hyperpermeable vasculature. In xenograft studies, FID reduced or limited tumor growth in multiple tumor types including lung, gastric, breast, pancreatic, and ovarian cancer. FID was more effective at lower or comparable taxane doses with fewer side effects. We present the first-in-human trial of FID. Methods: The study is evaluating the safety, PK, and efficacy of FID in pts with advanced solid tumors. The primary objective is to determine the MTD and RP2D. Pts received FID in doses between 15mg/m2 and 125mg/m2 using a standard 3+3 dose escalation design. FID was given IV on Days 1, 8, and 15 of a 28-day cycle. Eligibility included ECOG 0-2, adequate organ function, and no more than 3 prior lines of cytotoxic therapy for advanced disease. Results: Twenty-five pts were treated across 6 dose levels. Median age was 62 (44-76). ECOG PS was 2 in 1 pt and 1 in 64%. Median number of cycles was 2 (1-16). There were 2 DLTs of grade 3 rash at 100 mg/m2. Given the transient nature of the rash and response to topical therapy, DLT definition was modified to exclude grade 3 rash that lasts ≤ 7 days and additional patients were treated at 100 mg/m2 which was deemed tolerable. There was 1 DLT of grade 3 neutropenia at 125 mg/m2. All grade treatment related adverse events (TRAEs) in ≥ 25% of pts were rash (64%), alopecia (52%), pruritus (44%), anemia (44%) leukopenia, fatigue (40% each), dysgeusia, anorexia, nausea (32% each), and neutropenia (28%). Grade 3/4 TRAEs occurring in > 1 pt were anemia (20%), neutropenia, leukopenia, and maculopapular rash (16%). There were no treatment discontinuations due to toxicity. Twenty-two pts were evaluable for response by RECIST 1.1 with a PR rate of 14% (PR in pancreatic, biliary tract and NSCLC) and disease control rate of 59%. PK is linear and dose proportional. There is no paclitaxel accumulation after weekly dosing, and the t1/2 is between 18-26 hours. Conclusions: FID has a manageable safety profile with MTD not reached. Accrual is continuing at 125 mg/m2. PK is linear, dose proportional and comparable to that of nab-paclitaxel. There is preliminary evidence of anti-tumor activity in heavily pre-treated pts across different tumor types. Enrollment in dose escalation continues. Combination studies with immunotherapeutic agents are planned. Clinical trial information: NCT03537690.

Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12017-12017 ◽  
Author(s):  
F. Y. Lee ◽  
A. Camuso ◽  
S. Castenada ◽  
C. Flefleh ◽  
I. Ingio ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Lung Carcinoma ◽  
Therapeutic Potential ◽  
Single Agent ◽  
Human Colon ◽  
Maximum Tolerated Dose ◽  
Antitumor Efficacy ◽  
Efficacy Evaluation ◽  
Multiple Tumor ◽  
Tumor Types

12017 Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer. [Table: see text]

A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3013-3013 ◽  
Author(s):  
Michael Friedlander ◽  
Tarek Meniawy ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
Paul R. Harnett ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Multiple Tumor ◽  
Study Results

3013 Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

Phase I study of rucaparib and irinotecan in advanced solid tumors with homologous recombination deficiency (HRD) mutations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3513-3513
Author(s):  
Mallika Sachdev Dhawan ◽  
Roshun Rahimi ◽  
Silpa Karipineni ◽  
Lauren Wilch ◽  
Erika Zigman ◽  
...  
Keyword(s):  
Small Bowel ◽  
Phase I ◽  
Solid Tumors ◽  
Ductal Adenocarcinoma ◽  
Advanced Solid Tumors ◽  
Peritoneal Cancer ◽  
Multiple Tumor ◽  
Combination Treatments ◽  
Small Bowel Carcinoma ◽  
Tumor Types

3513 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for multiple tumor types with HRD mutations. In efforts to prolong durations of response, combination treatments of PARPi and chemotherapy are being explored. However, expected overlapping toxicities have previously limited the tolerability of PARPi-chemotherapy combinations. Preclinical studies suggest that the inhibition of PARP will prevent the repair of topoisomerase induced DNA strand breaks. In this Phase I trial, we test whether pulse dosing and alternate treatment schedules of rucaparib and irinotecan are safe and tolerable. Methods: Rucaparib and irinotecan were dose escalated in a 3+3 design. Patients with advanced solid tumors and somatic or germline known or suspected pathogenic mutations in HRD were accepted on trial. 15 patients have been enrolled in 3 cohorts and treated with rucaparib 400 mg BID (days 1-7) and irinotecan 65 mg/m2 (cohort 1) or 100 mg/m2 (cohort 2) every 2 weeks or 100 mg/m2 every 3 weeks (cohort 2i). Results: Tumor types on trial are heterogeneous and include pancreatic ductal adenocarcinoma (PDAC: 3), cholangiocarcinoma, neuroendocrine carcinoma of the pancreas, ovarian cancer/primary peritoneal carcinoma (3), prostate cancer, small bowel carcinoma, squamous cell carcinoma of the tonsil, testicular cancer, triple negative breast cancer, and urothelial carcinoma. 14/15 patients had 3+ prior lines of therapy. Mutation types include: 7 ATM, 3 BRCA1, 3 BRCA2, 1 CHEK2, and 1 PALB2. All patients were previously exposed to platinum chemotherapies; 8/15 had progressive disease while on platinum. 5/15 patients had prior PARPi with progression. There were 3 DLT events, all of which were related to grade 3 or 4 neutropenia. Of the 13 patients evaluable for response, there was one confirmed partial response (PR). 5 patients have remained on study for longer than 6 months and 3 patients with ATM mutations have remained on study for longer than one year (primary peritoneal cancer, small bowel carcinoma, PNET). 4/5 patients with clinical benefit had prior platinum progression and 1/5 had previously progressed on a PARPi. Our current recommended phase 2 dose is rucaparib 400 mg BID days 1-7 and irinotecan 100 mg/m2 every 3 weeks. Conclusions: The pulse dosing schedule of rucaparib and irinotecan has allowed for long term tolerability and exposure to both agents with encouraging efficacy in patients with ATM mutations. Further testing of PARPi and topoisomerase inhibitors at this schedule in patients with ATM mutations is planned. Clinical trial information: NCT03318445 .

Results of phase I clinical trials of Coramsine in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2070-2070
Author(s):  
M. Millward ◽  
A. Powell ◽  
P. Daly ◽  
S. Tyson ◽  
R. Ferguson ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Single Agent ◽  
Unknown Primary ◽  
Pharmacokinetic Parameters ◽  
Membrane Glycoproteins ◽  
Phase I Clinical Trials ◽  
Minor Response ◽  
Phase Ii Studies

2070 Background: Coramsine (C) is a 1:1 mixture of solasonine and solamargine, plant glycoalkaloids found in the species Solanum Linneanum, with single agent and synergistic combination in vitro and in vivo preclinical efficacy in various tumor models through interaction with rhamnose-containing cell membrane glycoproteins and subsequent internalization. Methods: C initially as a 2-hr IV infusion daily × 5 every 2 weeks to define the MTD, recommended Phase II dose, toxicity and pharmacokinetics. Based on preclinical toxicology the infusion duration was increased to 4 hours and 24 hours (120 hr continuous infusion). Doses studied range from 0.75 mg/kg/day to 3.0 mg/kg/day. Results: 27 pts were treated. DLT occurred in 2/2 pts at 1.5 mg/kg/day (2 hr) and 2/2 pts each at 3.0 mg/kg/day (4 hr and 24 hr). Preceding dose levels 1.0 mg/kg (2 hr) and 1.5 mg/kg (4 hr) produced DLT in 2/6 pts each with no grade IV. Over 24 hr, 2.25 mg/kg/day produced DLT in 4/6 patients. Limiting toxicity at all schedules was grade III/IV transaminitis with grade I-III increases of bilirubin and grade I-II creatinine. Hepatotoxicity was maximal at days 3–5, resolved over 10–21 days, was clinically asymptomatic apart from grade I-II fatigue, and was not cumulative. No myelosuppression or other serious drug-related toxicity was recorded. Partial responses were documented in 2 pts (renal, NSCLC) and minor response in 1 pt with unknown primary. Responses were seen using both 2 hr and 4 hr infusions. Pharmacokinetic parameters for solasonine and solamargine are linear across the narrow range of doses studied with elimination T1/2 of 5.57 ± 1.27 hr (solasonine), 8.40 ± 2.00 hr (solamargine) and Cl of 5.6 ± 1.6 L/hr (solasonine), 3.0 ± 0.7 L/hr (solamargine). Peak levels of both exceed active in vitro levels (>2,000 ng/ml). Conclusions: Coramsine produces dose-limiting hepatotoxicity at doses above 1.0 mg/kg/day over 2 hours or 1.5 mg/kg/day over 4 hours. 2.25 mg/kg/day over 24 hours exceeds the MTD. Activity has been seen against resistant solid tumors. Phase II studies in renal cancer and melanoma will be performed using 1.5 mg/kg/day over 4 hours. [Table: see text]

Phase (Ph) I/II study of investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Updated ph II results in patients (pts) with small cell lung cancer (SCLC), non-SCLC (NSCLC), breast cancer (BrC), head and neck squamous cell carcinoma (HNSCC), and gastroesophageal cancer (GE).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 605-605 ◽  
Author(s):  
Bohuslav Melichar ◽  
Antoine Adenis ◽  
Libor Havel ◽  
Albert C. Lockhart ◽  
Jaafar Bennouna ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Study Drug ◽  
Progression Free Survival ◽  
Hematologic Malignancies ◽  
Aurora A Kinase ◽  
Stage Design ◽  
Secondary Endpoints ◽  
Ecog Ps ◽  
Tumor Types

605 Background: MLN8237 is an investigational oral AAK inhibitor being evaluated in pts with hematologic (Ph III) and non-hematologic malignancies. We report here Ph II results from a, 5-arm study of single agent MLN8237 in pts with advanced, predominantly refractory, solid tumors (NCT01045421; closed for enrolment). Methods: Pts ≥18 years with relapsed/refractory disease measurable by RECIST, ECOG PS 0–1, and ≤2 prior (≤4 for BrC pts) cytotoxic chemotherapy regimens were enrolled. Pts with stable brain metastases were eligible. Pts were treated at the recommended Ph II dose; 50 mg BID for 7 d in 21-d cycles. For each cohort, a Simon’s 2-stage design was employed for Ph II, with ≥2 responses required in the first 20 response-evaluable pts to proceed to stage 2. The primary endpoint was overall response rate (ORR) by RECIST v1.1; safety and progression-free survival (PFS) were key secondary endpoints. Results: As of Dec 2012, 47 SCLC, 23 NSCLC, 49 BrC, 45 HNSCC and 47 GE pts in Ph II were response-evaluable (median age, 61 yrs [range 30–88]). NSCLC did not proceed to stage 2. ORR was 9%, 6%, and 4% in HNSCC, GE, and NSCLC pts, respectively; median PFS was 2.7, 1.5 and 3.1 months. BrC and SCLC data are shown in the Table. 92% of pts had a drug-related adverse event (DRAE). 57% of pts had Gr ≥3 DRAEs; including neutropenia (38%), anemia (10%), stomatitis (8%), and thrombocytopenia (6%). 22 pts died during the study; none were study-drug related. Conclusions: Single-agent activity of MLN8237 was evaluated across a range of solid tumors with a manageable toxicity profile. Encouraging Ph2 data in BrC and SCLC pts suggest that MLN8237 warrants further evaluation in these tumor types. Clinical trial information: NCT01045421. [Table: see text]

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) on overall survival (OS), progression free survival (PFS) and disease control rate (DCR) in patients with metastatic colorectal cancer (mCRC) from the RECOURSE study.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 744-744 ◽  
Author(s):  
Guillem Argiles ◽  
Takayuki Yoshino ◽  
Atsushi Ohtsu ◽  
Robert J. Mayer ◽  
Robert Winkler ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Ethnic Origin ◽  
Exact Test ◽  
Multiple Tumor ◽  
Number Of Patients ◽  
Immune Response To Cancer ◽  
Cox Analysis ◽  
Metastatic Sites ◽  
Ecog Ps ◽  
Tumor Types

744 Background: Elevated neutrophil-to-lymphocyte (NLR) ratios may represent markers of a suboptimal host immune response to cancer and have been shown to correlate with prognosis in multiple tumor types. Trifluridine/tipiracil (FTD/TPI also known as TAS-102) compared with placebo significantly improved OS (median: 7.1 vs.5.3 months, hazard ratio (HR) = 0.68, 95% confidence interval (CI) [0.58;0.81], p < 0.0001), PFS, and DCR in the phase 3 RECOURSE study, conducted in patients with refractory mCRC. A post-hoc analysis was conducted to assess correlation between clinical outcomes and baseline NLR (in blood) in RECOURSE. Methods: A retrospective review on 782/800 patients, with available NLR, was performed on OS, PFS, and DCR in two subgroups of patients with low ( < 3) or high (≥ 3) NLR at baseline. Based on literature, the cutoff value of 3 was chosen as the number of patients was similar in each NLR subgroup. Between-group comparison was performed using a stratified Cox’s proportional hazard model for OS and PFS, and Fisher’s Exact test for DCR. Results: The median value of NLR at baseline was similar in each group, FTD/TPI (N = 519): 4.4 ± 6.3, placebo (N = 263): 4.7 ± 6.5. Almost 60% of patients in each group had high NLR. In the low NLR vs. high NLR subgroup, there were differences at baseline for ethnic origin (Asian: 45% vs.29%), ECOG PS 0 (69% vs. 49%), and number of metastatic sites ≥ 3 (32% vs. 46%). The median OS [95 % CI] was statistically significantly higher in the low vs. high NLR subgroup: 8.4 [7.8;9.5] vs. 5.3 [4.7;5.7] months, HR = 0.49, 95% CI [0.41;0.59], p < 0.0001. Irrespective of NLR, all patients benefited from FTD/TPI vs. placebo. The results of PFS and DCR were statistically significantly better in the low NLR vs. high NLR subgroup. The multivariate Cox analysis for OS with the interaction test between treatment groups and NLR showed that NLR is not a predictive factor (p = 0.15). Conclusions: In this retrospectively analyzed mCRC population, NLR was shown to be an independent prognostic factor. Further research is warranted to assess if NLR can be a stratification factor in mCRC clinical trials. Clinical trial information: NCT01607957.

Association of LRP1B pathogenic genomic alterations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3007-3007 ◽  
Author(s):  
Landon Carter Brown ◽  
Ramy Sedhom ◽  
Eric B Schwartz ◽  
Jason Zhu ◽  
Chester Kao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Density Lipoprotein ◽  
Primary Objective ◽  
Missense Mutations ◽  
Multiple Tumor ◽  
Tumor Types

3007 Background: Low-density lipoprotein receptor-related protein 1b (LRP1b) is a putative tumor suppressor and one of the most frequently altered genes in cancer. Our prior single-center work suggested that LRP1B alterations may enrich for responses to immune checkpoint inhibitors (ICI) in solid tumors including prostate cancer; however, validation of these findings is needed. Methods: We conducted a multicenter, retrospective analysis of patients with LRP1B alterations (on tissue-based next-generation sequencing panels) treated with ICI at Duke, Johns Hopkins (JHU), and University of Michigan (UM). The primary objective was to assess the association between objective response rate (ORR) to ICI and pathogenic LRP1B alterations, defined as deletions or truncating alterations, when compared with LRP1B variants of undetermined significance (VUS), defined as missense mutations not predicted to be pathogenic in COSMIC. Missense changes with a COSCMIC FATHMM score of > 0.8 were categorized separately as likely pathogenic. Summary statistics, ORR, progression free survival (PFS), and overall survival (OS) were calculated. Results: 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations were treated with ICI. Median age was 61 (range 32-82). The most common tumor types by alteration (pathogenic or likely pathogenic/VUS%) were lung (33/47%), GI (17/13%), prostate (11/7%), sarcoma (2/9%), melanoma (11/0%), and others (26/24%). 93% of patients received single-agent PD-(L)1 inhibition. The ORR for patients with either pathogenic/likely pathogenic alterations, or VUS alterations was 57% and 18%, respectively. After excluding MSI-high or TMB-high ( > 10 mut/Mb) tumors, ORR was 14/25 (56%) and 6/36 (17%), respectively. Pathogenic or likely pathogenic LRP1B alterations were associated with longer PFS (HR 0.39, 95% CI 0.24-0.63) and OS (HR 0.58, 95% CI 0.36-0.95). Conclusions: This multicenter study shows impressive and durable objective response rates to ICI for patients harboring pathogenic LRP1B alterations when compared to those with LRP1B VUS, independent of TMB/MSI status. Further mechanistic insights and prospective validation studies are warranted. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document