scholarly journals Larotrectinib: A Novel Tumor-Agnostic Neurotrophic Tropomyosin Receptor Kinase (NTRK) Inhibitor in Advanced Solid Tumors

2021 ◽  
Author(s):  
Manikandan Dhanushkodi ◽  
Jyoti Bajpai
Keyword(s):  
Solid Tumors ◽  
Response Rate ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Receptor Kinase ◽  
Phase 3 ◽  
Free Survival ◽  
Randomized Controlled ◽  
Fusion Inhibitors ◽  
Neuropsychiatric Manifestations

AbstractLarotrectinib and entrectinib are highly selective, potent tropomyosin receptor kinase fusion inhibitors. It is U.S. Food and Drug Administration approved for the treatment of adult and pediatric advanced solid tumors with neurotrophic tropomyosin receptor kinase fusion genes who are refractory to standard systemic therapy. The response rate was ~80% and was rapid and durable. The median progression-free survival was 28 months. The side effects include anemia, weight gain, hepatotoxicity, and neuropsychiatric manifestations. Phase 3, randomized controlled trials are warranted to assess survival benefit.

Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors

2017 ◽  
Vol 35 (18) ◽  
pp. 2028-2036 ◽  
Author(s):  
Howard A. Burris ◽  
Jeffrey R. Infante ◽  
Stephen M. Ansell ◽  
John J. Nemunaitis ◽  
Geoffrey R. Weiss ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Costimulatory Molecule ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Free Survival ◽  
Metastatic Rcc

Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity—grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation—chemokine induction, T-cell stimulation, regulatory T cell depletion—was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3295-3301 ◽  
Author(s):  
Marinus H. J. van Oers ◽  
Richard Klasa ◽  
Robert E. Marcus ◽  
Max Wolf ◽  
Eva Kimby ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Remission Induction ◽  
Phase 3 ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Rituximab Maintenance ◽  
Non Hodgkin Lymphoma

Abstract We evaluated the role of rituximab (R) both in remission induction and maintenance treatment of relapsed/resistant follicular lymphoma (FL). A total of 465 patients were randomized to induction with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (every 3 weeks) or R-CHOP (R: 375 mg/m2 intravenously, day 1). Those in complete remission (CR) or partial remission (PR) were randomized to maintenance with R (375 mg/m2 intravenously once every 3 months for a maximum of 2 years) or observation. R-CHOP induction yielded an increased overall response rate (CHOP, 72.3%; R-CHOP, 85.1%; P < .001) and CR rate (CHOP, 15.6%; R-CHOP, 29.5%; P < .001). Median progression-free survival (PFS) from first randomization was 20.2 months after CHOP versus 33.1 months after R-CHOP (hazard ratio [HR], 0.65; P < .001). Rituximab maintenance yielded a median PFS from second randomization of 51.5 months versus 14.9 months with observation (HR, 0.40; P < .001). Improved PFS was found both after induction with CHOP (HR, 0.30; P < .001) and R-CHOP (HR, 0.54; P = .004). R maintenance also improved overall survival from second randomization: 85% at 3 years versus 77% with observation (HR, 0.52; P = .011). This is the first trial showing that in relapsed/resistant FL rituximab maintenance considerably improves PFS not only after CHOP but also after R-CHOP induction.

Progression-Free Survival Ratio As End Point for Phase II Trials in Advanced Solid Tumors

2011 ◽  
Vol 29 (15) ◽  
pp. e451-e452 ◽  
Author(s):  
Marc Buyse ◽  
Emmanuel Quinaux ◽  
Alain Hendlisz ◽  
Vassilis Golfinopoulos ◽  
Christophe Tournigand ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Survival Ratio ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Free Survival ◽  
End Point

scholarly journals Augmenting the randomized controlled trial with real-world data to aid clinical decision making in metastatic renal cell carcinoma: a systematic review and meta-analysis

2019 ◽  
Vol 15 (34) ◽  
pp. 3987-4001 ◽  
Author(s):  
Michael Moran ◽  
Dana Nickens ◽  
Katherine Adcock ◽  
Meg Bennetts ◽  
Natalie Charnley ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Median Overall Survival ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Real World Data ◽  
Free Survival ◽  
Median Progression Free Survival ◽  
Randomized Controlled

Aim: To evaluate how efficacy outcomes from real-world data (RWD) can support those from randomized controlled trials (RCTs), in the context of first-line tyrosine kinase inhibitor treatment of metastatic renal cell carcinoma. Patients & methods: PubMed, Ovid, MEDLINE and EMBASE were searched for RCTs and RWD studies with ≥50 adult patients per arm published in 2000–2017. Outcome measures were median progression-free survival, median overall survival and objective response rate. Results: A total of 13 RCTs and 22 RWD studies met eligibility criteria; 31, 28 and 25 studies, respectively, reported median progression-free survival, median overall survival and objective response rate. Summary outcome measures were similar in RWD and RCTs. Conclusion: RWD validates efficacy-based outcomes from RCTs and may provide supportive evidence to inform clinical decisions.

scholarly journals Checkpoint inhibition in combination with an immunoboost of external beam radiotherapy in solid tumors (CHEERS): study protocol for a phase 2, open-label, randomized controlled trial

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mathieu Spaas ◽  
Nora Sundahl ◽  
Eva Hulstaert ◽  
Vibeke Kruse ◽  
Sylvie Rottey ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Treatment Schedule ◽  
Advanced Solid Tumors ◽  
Cell Lung Carcinoma ◽  
Free Survival ◽  
Link Type ◽  
Study Results

Abstract Background While the introduction of checkpoint inhibitors (CPIs) as standard of care treatment for various tumor types has led to considerable improvements in clinical outcome, the majority of patients still fail to respond. Preclinical data suggest that stereotactic body radiotherapy (SBRT) could work synergistically with CPIs by acting as an in situ cancer vaccine, thus potentially increasing response rates and prolonging disease control. Though SBRT administered concurrently with CPIs has been shown to be safe, evidence of its efficacy from large randomized trials is still lacking. The aim of this multicenter randomized phase II trial is to assess whether SBRT administered concurrently with CPIs could prolong progression-free survival as compared to standard of care in patients with advanced solid tumors. Methods/design Ninety-eight patients with locally advanced or metastatic disease will be randomized in a 1:1 fashion to receive CPI treatment combined with SBRT (Arm A) or CPI monotherapy (Arm B). Randomization will be stratified according to tumor histology (melanoma, renal, urothelial, head and neck squamous cell or non-small cell lung carcinoma) and disease burden (≤ or > 3 cancer lesions). The recommended SBRT dose is 24Gy in 3 fractions, which will be administered to a maximum of 3 lesions and is to be completed prior to the second or third CPI cycle (depending on CPI treatment schedule). The study’s primary endpoint is progression-free survival as per iRECIST. Secondary endpoints include overall survival, objective response, local control, quality of life and toxicity. Translational analyses will be performed using blood, fecal and tissue samples. Discussion: The CHEERS trial will provide further insights into the clinical and immunological impact of SBRT when combined with CPIs in patients with advanced solid tumors. Furthermore, study results will inform the design of future immuno-radiotherapy trials. Trial registration Clinicaltrials.gov identifier: NCT03511391. Registered 17 April 2018.

scholarly journals Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors

2017 ◽  
Vol 35 (12) ◽  
pp. 1304-1311 ◽  
Author(s):  
Andrew J. Wagner ◽  
Udai Banerji ◽  
Amit Mahipal ◽  
Neeta Somaiah ◽  
Heather Hirsch ◽  
...  
Keyword(s):  
Partial Response ◽  
Mrna Expression ◽  
Solid Tumors ◽  
Drug Exposure ◽  
Progression Free Survival ◽  
Apparent Volume ◽  
Clinical Activity ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Free Survival

Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 μM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2 = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.

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