Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies

2019 ◽  
Vol 60 (4) ◽  
pp. 515-527 ◽  
Author(s):  
Anne‐Gaelle Dosne ◽  
Elodie Valade ◽  
Kim Stuyckens ◽  
Lilian Y. Li ◽  
Daniele Ouellet ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Population Pharmacokinetics ◽  
Cancer Patients ◽  
Phase 1 ◽  
Phase 2

scholarly journals Oral Administration of Mavorixafor, a CXCR4 Antagonist, Increases Peripheral White Blood Cell Counts across Different Disease States

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2186-2186
Author(s):  
David C. Dale ◽  
Steven P. Treon ◽  
David F. McDermott ◽  
Diego Cadavid ◽  
Xia Luo ◽  
...  
Keyword(s):  
Oral Administration ◽  
Healthy Volunteers ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Publicly Traded ◽  
Whim Syndrome ◽  
Phase 2 Trial ◽  
Phase 1B ◽  
Wbc Count

Abstract Introduction: Peripheral leukocyte deficiency is a common feature of multiple diseases and may render affected individuals susceptible to infections, both common and opportunistic. The CXCR4 chemokine receptor regulates the trafficking of leukocytes among the bone marrow, blood, and lymphatic system (Al Ustwani O, et al. Br J Haematol. 2014;164:15-23). Mavorixafor is an orally available investigational, small-molecule, selective antagonist of the CXCR4 receptor with potential to restore physiological trafficking and maturation of white blood cells (WBCs). Mavorixafor was previously shown to increase totals and subsets of WBCs in healthy volunteers and in a phase 2 clinical trial in adults with WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) syndrome (Stone N, et al. Antimicrob Agents Chemother. 2007;51(7):2351-2358; Dale D, et al. Blood. 2020;136(26):2994-3003). Here, we report the effect of daily oral administration of mavorixafor on peripheral WBC counts and subsets in patients with clear cell renal cell carcinoma (ccRCC), WHIM syndrome, and Waldenström's macroglobulinemia (WM). Methods: Percentage changes in total peripheral WBC count, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and absolute monocyte count (AMC) from pretreatment levels were evaluated in the following settings: a phase 1/2 trial evaluating mavorixafor (200 mg twice daily or 400 mg once daily [QD]) in combination with axitinib (5 mg twice daily) in patients with advanced ccRCC who received ≥1 prior therapy; a phase 1b trial evaluating mavorixafor (400 mg QD) in combination with nivolumab (240 mg QD) in patients with metastatic ccRCC unresponsive to prior nivolumab monotherapy; a long-term extension of the aforementioned phase 2 trial evaluating mavorixafor 300 or 400 mg QD in patients with WHIM syndrome with pathogenic CXCR4 gain-of-function mutation and ANC ≤400/μL and/or ALC ≤650/μL; and an ongoing phase 1b trial evaluating mavorixafor (200 mg QD for 4 weeks, increased to 400 mg and 600 mg QD thereafter) in combination with ibrutinib (420 mg QD) in patients with WM with MYD88 and CXCR4 mutations. Results: In the study evaluating combination mavorixafor (400 mg QD) and axitinib in ccRCC, total WBC count, ANC, ALC, and AMC increased to 153%, 158%, 143%, and 182% of baseline after 4 weeks (n=49), and with increases sustained at 159%, 171%, 139% and 166% of baseline after 6 months' treatment (n=20). In the study evaluating mavorixafor in combination with nivolumab in ccRCC, total WBC count, ANC, ALC, and AMC increased to 146%, 143%, 141%, and 179% of baseline after 4 weeks (n=9), and with increases sustained at 147%, 136%, 152%, and 191% of baseline after 6 months (n=2). In an interim analysis of the phase 1b trial in WM, compared to screening values, total WBC count, ANC, ALC, and AMC increased to 192%, 170%, 219%, and 186% of baseline after 4 weeks (n=8), and with increases sustained at 163%, 192%, 106%, 172% of baseline after 6 months' (n=5) treatment. In the WHIM syndrome phase 2 extension, total WBC count, ANC, ALC, and AMC increased to 339%, 652%, 239%, and 486% of baseline after 6 months' (n=5) treatment, with annualized infection rate decreasing from 5.6 (SD ± 3.13) events at baseline to 2.2 (SD ± 0.93) events after 40 months. Mavorixafor was generally well tolerated, with manageable safety profile across all indications either alone or in combination with other drugs. Conclusions: Mavorixafor alone or in combination with other therapies is the first oral treatment to either acutely or chronically increase total peripheral WBCs 1.5- to 3-fold and WBC subsets across all disease populations examined, in both the presence (WHIM syndrome and WM) and absence (ccRCC and healthy volunteers) of CXCR4 gain-of-function mutation. Increases in WBC subsets occurred rapidly and were sustained during chronic treatment, with a larger treatment effect in patients with pre-existing cytopenia (WHIM syndrome) compared to patients without cytopenia at baseline (ccRCC and WM). Co-occurring reduction in infection burden was observed in the phase 2 trial in WHIM syndrome. Assessment of the beneficial effects of mavorixafor on total and WBC subsets is ongoing in a phase 3 trial of WHIM syndrome and a phase 1 trial of severe chronic neutropenia (SCN) that will assess the potential to correct cytopenias by elevating total WBC counts. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Treon: AbbVie: Consultancy, Research Funding; Dana Farber Cancer Institute: Current Employment; Self: Patents & Royalties: Holder of multiple patents related to testing and treatment of MYD88 and CXCR4 mutated B-cell malignancies; BMS: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; X4: Research Funding. McDermott: Johnson and Johnson: Consultancy, Honoraria; Genentech: Research Funding; Eisia Inc.: Consultancy, Honoraria; Werewolf Therapeutics: Consultancy, Honoraria; Calithera Biosciences: Consultancy, Honoraria; X4 Pharmaceuticals: Research Funding; Iovance: Consultancy, Honoraria; EMD Serono: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Exelixis: Research Funding; Alkermes, Inc.: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Luo: X4 Pharmaceuticals: Consultancy. Garg: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chen: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Taveras: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Bhandari: X4 Pharmaceuticals: Current Employment.

Phase 1 study of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in East Asian cancer patients: pharmacokinetics and recommended phase 2 dose

2015 ◽  
Vol 33 (4) ◽  
pp. 942-953 ◽  
Author(s):  
Karthik Venkatakrishnan ◽  
Tae Min Kim ◽  
Chia-Chi Lin ◽  
Lim Soon Thye ◽  
Wee Joo Chng ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
East Asian ◽  
Aurora A Kinase ◽  
Phase 2 ◽  
Aurora A ◽  
Phase 1 Study

The cognitive effects of modafinil in breast cancer survivors: A randomized clinical trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9004-9004 ◽  
Author(s):  
S. Kohli ◽  
S. G. Fisher ◽  
Y. Tra ◽  
K. Wesnes ◽  
G. R. Morrow
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Cancer Patients ◽  
Phase 1 ◽  
Secondary Memory ◽  
Phase 2 ◽  
Breast Cancer Patients ◽  
Memory And Attention

9004 Background: Patients receiving treatment for cancer can experience a diminution of their cognitive abilities which can persist for many years after. The present study examined the potential of modafinil as a cognitive enhancer on memory and attention in a randomized clinical trial in breast cancer patients following completion of treatment. Methods: Breast cancer patients who reported a score of = 2 on the Brief Fatigue Inventory (BFI) an average of 22.8 months following completion of chemotherapy were enrolled. In Phase 1, patients received 200mg modafinil open-label once daily for 4 weeks. In Phase 2, patients with a positive response following Phase 1 were randomized either to an additional 4 weeks of modafinil or to placebo. Tests of memory and attention selected from the Cognitive Drug Research (CDR) computerized cognitive assessment were performed at baseline (before modafinil) and after completing Phase 1 and 2. The difference between scores at baseline and scores at Phase 1 and Phase 2, were subjected to a Wilcoxon's signed rank test. Results: Of the 82 women enrolled, 68 completed all 3 CDR assessments in the study (range=33–83 years, median age=54 years). At the end of Phase 1 (week 4), modafinil had a significant effect on the Speed of Memory Index (p=0.0047) and the Digit Vigilance Test (p=0.0014) but showed no significant effect on Quality of Working Memory (p=0.3528) nor on Power of Attention (p=0.8953). At the end of phase 2 (week 8), the group that continued modafinil demonstrated improved Mean Continuity of Attention (p=0.0002) compared with the placebo group and also demonstrated significantly greater improvements in Quality of Episodic Secondary Memory relative to placebo (p<0.005). This improvement was observed at week 4, and was maintained throughout the study. Finally, continued modafinil demonstrated significantly greater improvement in Speed of Memory relative to placebo (p=0.009). Conclusions: Modafinil provides significant improvements in attention and speed of memory for breast cancer patients following their treatment of cancer. Although further study is needed, these findings suggest that modafinil may enhance quality of life in this patient population. Supported by a grant from Cephalon, Inc and NCI Grants U10-CA37420 and R25- CA102618. No significant financial relationships to disclose.

scholarly journals Cultural Adaptation and Validity of the Sniffin’ Sticks Psychophysical Test for the UK Setting

2021 ◽  
Author(s):  
Lorna Langstaff ◽  
Allan Clark ◽  
Mahmoud Salam ◽  
Carl M. Philpott
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Intraclass Correlation ◽  
Olfactory Dysfunction ◽  
Phase 2 ◽  
Olfactory Testing ◽  
Identification Score ◽  
Identification Test ◽  
The Uk ◽  
Tdi Score

Abstract Introduction Olfactory testing must be culturally adapted to be relevant to the target population. This study aimed to validate the Sniffin’ Sticks test for the UK setting. Methods A cohort study was conducted at a tertiary olfactory dysfunction clinic. Phase 1—healthy volunteers underwent the original German identification test followed by a UK adapted version. Phase 2—patients with olfactory dysfunction underwent the extended smell test (TDI) including the new descriptors. Outcome measures included differences in identification test (phase 1), retest reliability and differences in scores before and after treatment. Results A total of 31 healthy volunteers and 87 patients were recruited (6 and 31 males, respectively). Phase 1—mean identification scores showed a small improvement after descriptor adaptations (13.77 and 14.57, p = 0.0029). Phase 2—41 untreated participants had a mean identification score of 7.31 at both intervals (95% CI: − 1.15 to 1.15, p > 0.999). The mean change in treated participants was 1.88 (0.70 to 3.06, p = 0.0224). TDI score difference between treated and untreated groups was 6.63 (2.48 to 10.79, p = 0.0023). The intraclass correlation coefficient for untreated patients was high for both TDI score (ICC = 0.82, 95% CI 0.57 to 0.93) and identification score (ICC = 0.80, 0.52 to 0.93); CIs suggest the reliability is moderate to excellent. Conclusions This study confirms the validity of the descriptor adaptations of the identification component of the Sniffin’ Sticks test to distinguish between health and disease. Implications The Sniffin’ Sticks test can now reliably be used for clinical assessment of British patients, modifying only the descriptors.

Safety Profile of AMG 531 in Healthy Volunteers and in Thrombocytopenic Patients with Immune Thromobocytopenic Purpura.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1240-1240 ◽  
Author(s):  
Daniel E. Stepan ◽  
Elaine Sergis-Deavenport ◽  
Reggie Kelly ◽  
Jenny Christal ◽  
Chien-Feng Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Safety Profile ◽  
Phase 1 ◽  
Phase 2 ◽  
Platelet Response ◽  
Open Label ◽  
Two Phase ◽  
Open Label Extension

Abstract AMG 531 is a novel platelet-stimulating peptibody that targets the thrombopoietin (TPO) receptor, resulting in an increased production of platelets. AMG 531 lacks sequence homology to native TPO. To date, AMG 531 has been administered in two phase 1 studies in a total of 56 healthy volunteers and in three phase 2 studies, with the option to continue in an open-label extension study, in a total of 57 patients with immune thrombocytopenic purpura (ITP). In general, no deaths or detectable neutralizing antibodies have occurred across the AMG 531 development program. In the two phase 1 studies, AMG 531 increased platelet counts in a dose-response manner when administered as a single subcutaneous (SC) or intravenous (IV) dose of ≥ 1.0 μg/kg. The dynamics of the platelet response were as expected based on experience with other Mpl ligands. Single doses of AMG 531 ≤ 10.0 μg/kg were well tolerated. No deaths, serious or severe adverse events, or other events of clinical importance were reported at any dose administered (0.1, 0.3, 1.0, and 2.0 μg/kg SC; 0.3, 1.0, and 10.0 μg/kg IV). Commonly reported adverse events in healthy subjects receiving AMG 531 were mild to moderate headache (13% incidence in both studies), malaise/fatigue (4% and 6%), and various flu-like reactions. In the phase 2 studies in patients with ITP, AMG 531 was administered SC using weight-based dosing in all but one study. The maximum dose administered (in the extension study) was 23 μg/kg; most patients received doses of 3 to 9 μg/kg. AMG 531 has been administered as frequently as weekly for &gt; 24 weeks. To date, three studies have been completed: two studies of two administrations on day 1 and 15, administered as unit (μg) doses in one study (N=16 and N=24, respectively), one placebo-controlled study of 6 weeks’ duration with weekly dosing (AMG 531 N=17; placebo N=4). One open-label extension (N=26) is ongoing. AMG 531 has been generally well tolerated in ITP patients. Most of the reported adverse events have been mild to moderate in severity; no dose-related trends have been observed. Across the four studies, the most commonly reported adverse events in patients receiving AMG 531 were headache (29%–54% incidence), contusion (15%–53%), and epistaxis (13%–41%). In the 6-week, weekly-dosing study, contusion and epistaxis were each reported for 50% and 41% of placebo-treated patients, respectively. Across the phase 2 studies, five patients treated with AMG 531 have experienced serious adverse events deemed as serious, unexpected, and reported as related to study drug. These include worsening of thrombocytopenia in three patients after completing treatment, headache and elevated LDH in one patient, and diffuse reticulin formation in the bone marrow reported as myelofibrosis in one patient. The reticulin formation is hypothesized to be due to an excessive accumulation of megakaryocytes in the bone marrow. AMG 531 was discontinued, and a follow-up bone marrow (after 3 months) showed improvement in reticulin. In summary, AMG 531 has been generally well tolerated and able to stimulate platelet production in a dose-response manner in healthy volunteers and ITP patients. Results suggest that both unit dosing and weight-based dosing provide a predictable platelet response. AMG 531 may represent a new treatment option for thrombocytopenic patients with ITP. Safety surveillance is ongoing to further establish the safety profile of AMG 531.

scholarly journals Surgical management of oncologic patient during and after the COVID-19 outbreak: practical recommendations from the Italian society of Surgical Oncology

2020 ◽  
Author(s):  
Davide Cavaliere ◽  
◽  
Dario Parini ◽  
Luigi Marano ◽  
Federica Cipriani ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Phase 1 ◽  
Surgical Oncology ◽  
Minimal Invasive ◽  
Italian Society ◽  
Phase 2 ◽  
Energy Devices ◽  
Oncologic Patients ◽  
Phase Phase ◽  
Practical Recommendations

AbstractThe recent outbreak of COVID-19 in Italy caused a limitation of the resources of the health system, which necessarily led to their rationalization in the critical phase (phase 1) and a reorganization of the system in the following phase (phase 2). The Italian Society of Oncological Surgery–SICO has drafted these practical recommendations, calibrated on the most recent scientific literature and taking into account current health regulations and common sense. Surgical activity during phase 1 and 2 should follow a dynamic model, considering architectural structures, hospital mission, organizational models. Surgical delay should not affect oncological prognosis. However, COVID-19-positive cancer patients should be postponed until the infection is cured. The patients to consider more carefully before delaying surgery are those who have completed neoadjuvant therapy, patients with high biological aggressiveness tumors or without therapeutic alternatives. The multidisciplinary discussions are fundamental for sharing clinical decisions; videoconference meetings are preferable and use of telemedicine for follow-up is recommended. Especially in phase 1, maximum effort must be made to reduce the spread of the pandemic. Prefer intra-corporeal rather than open anastomosis during laparoscopy and mechanical rather than hand-sewn anastomosis in open surgery. Consider PPE for caregivers during stoma management. Minimal invasive surgery is not discouraged, because there is little evidence for augmented risk. Specific procedures have to be followed and use of energy devices has to be limited. Training programs with COVID-19 + patients are not recommended. All staff in OR should be trained with specific courses on specific PPE use. Differentiate recommendations are presented for every district cancer. Surgical oncology during phase 2 should be guaranteed by individual and distinct protocols and pathways between cancer patients and COVID-19 + patients with resources specifically addressed to the two distinct kind of patients to limit diagnostic/therapeutic interferences or slowdowns. These recommendations are based on currently available evidence about management of oncologic patients during COVID-19 pandemic, were endorsed by the SICO Executive Board, and are considered suitable for nationwide diffusion. They will be subject to updates and revisions in case of new and relevant scientific acquisitions.

scholarly journals Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Huijie Bian ◽  
Zhao-Hui Zheng ◽  
Ding Wei ◽  
Aidong Wen ◽  
Zheng Zhang ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Lung Tissue ◽  
Phase 1 ◽  
Area Under The Curve ◽  
Blood Pool ◽  
Control Group ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Phase 2 Study

AbstractsRecent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019 (COVID-19) patients. Here, we conducted a randomized, double-blinded, placebo-controlled phase 1 trial to evaluate the safety, tolerability, and pharmacokinetics of meplazumab in healthy subjects, and an open-labeled, concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients. In phase 1 study, 59 subjects were enrolled and assigned to eight cohorts, and no serious treatment-emergent adverse event (TEAE) or TEAE grade ≥3 was observed. The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics. No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort. The biodistribution study indicated that meplazumab reached lung tissue and maintained >14 days stable with the lung tissue/cardiac blood–pool ratio ranging from 0.41 to 0.32. In the exploratory phase 2 study, 17 COVID-19 patients were enrolled, and 11 hospitalized patients were involved as concurrent control. The meplazumab treatment significantly improved the discharged (P = 0.005) and case severity (P = 0.021), and reduced the time to virus negative (P = 0.045) in comparison to the control group. These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.

Rationalization and internalization

2001 ◽  
Vol 60 (4) ◽  
pp. 215-230 ◽  
Author(s):  
Jean-Léon Beauvois
Keyword(s):  
Phase 1 ◽  
Facilitatory Effect ◽  
Phase 2 ◽  
Causal Explanations ◽  
Reduction Effect ◽  
Dissonance Reduction

After having been told they were free to accept or refuse, pupils aged 6–7 and 10–11 (tested individually) were led to agree to taste a soup that looked disgusting (phase 1: initial counter-motivational obligation). Before tasting the soup, they had to state what they thought about it. A week later, they were asked whether they wanted to try out some new needles that had supposedly been invented to make vaccinations less painful. Agreement or refusal to try was noted, along with the size of the needle chosen in case of agreement (phase 2: act generalization). The main findings included (1) a strong dissonance reduction effect in phase 1, especially for the younger children (rationalization), (2) a generalization effect in phase 2 (foot-in-the-door effect), and (3) a facilitatory effect on generalization of internal causal explanations about the initial agreement. The results are discussed in relation to the distinction between rationalization and internalization.

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