The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients (PTS) with advanced GI mid-gut neuroendocrine tumor (NET): Phase 2 results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4110-4110
Author(s):  
Daniel M. Halperin ◽  
Melissa Lynne Johnson ◽  
Jennifer A. Chan ◽  
Lowell L. Hart ◽  
Natalie Cook ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Phase 1 ◽  
Safety Data ◽  
Neuron Specific Enolase ◽  
Primary Objective ◽  
Somatostatin Analog ◽  
Entire Study ◽  
Safety And Efficacy ◽  
Grade 3

4110 Background: PEN-221 is a small molecule drug conjugate composed of a SSTR2 binding somatostatin analog linked to the toxin DM1. PEN-221-001 was a study which assessed the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-221 in well differentiated neuroendocrine tumors (NETs) and small cell lung cancer. Here we present the efficacy outcomes for patients enrolled in the GI mid-gut cohort and the safety data for the entire study. Methods: Pts with advanced, SSTR2+ (by imaging) GI mid-gut NETs were enrolled in this cohort of the study. The primary objective was to determine the safety and efficacy of PEN-221 given intravenously, every (q) 3 weeks in patients with documented radiographic progression within the 6 months prior to enrollment. Patients previously treatment with cytotoxic chemotherapy were excluded. Preliminary efficacy was assessed using RECIST 1.1. A clinically meaningful efficacy result was defined as a Clinical Benefit Rate (CBR) > 75% and a median progression-free survival (mPFS) > 8 months. Results: 32 patients (17M/15F) were enrolled between January 2018 to June 2020 and the data cut-off for this report is July 31, 2020. The first nine patients were treated at the phase 1 determined Maximum Tolerated Dose of 18 mg. After review of the safety, tolerability, and PK data from these pts, the regimen was amended to 8.8 mg/m2 for all subsequent pts to achieve more uniform exposures (AUC) across all pts and reduce toxicity in pts with lower body-surface areas (BSA). The mean number of cycles received by pts in this cohort was 7 (range 1-18), with 5 pts still on treatment at time of data lock. PEN-221 was well tolerated in all pts at the dose of 8.8 mg/m2. The most frequent (≥20% pts) PEN-221 related adverse events of any grade were fatigue (39%), nausea (38%), diarrhea (35%), decreased appetite (30%), infusion reaction (24%), AST/ALT/Alk Phos increase (24%), and peripheral neuropathy (21%). Only 14 (10%) of these events were grade 3 or greater. Grade 3 PEN-221 related adverse events which were reported in 2 or more pts included fatigue (7.6%), ALT/AST/Alk Phos increase (7.6%), and peripheral neuropathy (3%). PEN-221 plasma median t1/2 was ̃4.5 h, with exposures uniform using BSA based dosing. Of the 26 pts who were evaluable for response, 23 (88.5%) had stable disease (SD) reported as their best response with a CBR of 88.5%. Target lesion shrinkage was observed in 10 (38%) patients. The median PFS for this cohort was 9 months (CI 5 – 16.5 months). Tumor marker data (Neuron Specific Enolase, Chromogranin A, 5-Hydroxyindoleacetic Acid, and Circulating Tumor Cells) will also be presented. Conclusions: PEN-221 appears well tolerated at 8.8 mg/m2 q 3 weeks and has demonstrated efficacy exceeding its clinical efficacy goals with a CBR of 88.5% and a mPFS of 9 months. A randomized trial of PEN-221 in GI mid-gut NET patients is now in development. Clinical trial information: NCT02936323.

The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7505-7505
Author(s):  
Tycel Jovelle Phillips ◽  
Alexey Valeryevich Danilov ◽  
David Alan Bond ◽  
Alex Francisco Herrera ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Data ◽  
Standard Of Care ◽  
Primary Objective ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Grade 5 ◽  
Unrelated Condition ◽  
Mantle Cell ◽  
Grade 3

7505 Background: MCL is a rare lymphoma without a standard of care but several regimens have demonstrated clinical activity, the majority based on traditional chemotherapy. We hypothesized that adding venetoclax (V) to R2 would be safe and effective in MCL pts irrespective of age, morphology or stage. Here we present safety and efficacy data from the on-going phase 1b study of R2 + V in pts with newly diagnosed MCL. Methods: This multi-center phase 1 study (NCT03523975) enrolled pts aged ≥18 yrs with untreated MCL. The primary objective was to characterize the safety and tolerability of R2 + V and determine the MTD. During induction (12 months (m)) pts received lenalidomide (L) 20 mg daily on day 1-21, Rituximab (R) was given weekly during c1 then on day 1 of every even cycle, V was escalated over 4 weeks to 400 mg beginning day 8. Each cycle is 28 days (d). The DLT period was 42 d beginning C1D8. In maintenance, R every 8 weeks for 36m, L at 10 mg or half of last dose during induction for 24 m and V for minimum 12 m. No pts have been transplanted. Pts with progression (PD) came off study. MRD was analyzed in parallel with scans during induction by clonoSEQ assay (Adaptive Biotechnologies). Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts on study. Pt characteristics/responses are summarized in Table. Among the 28 pts who have received at least one dose, the median treatment duration so far is 278d (IQR 170-560), with 24 pts still on treatment (Tx). 1 pt is off from a unrelated condition. All pts escalated to V 400 mg w/o any DLTs noted. Treatment-emergent adverse events (TEAEs) were reported in 100% of pts, and grade 3+ TEAEs were reported in 26 (93%) patients. The most common all-grade TEAEs (≥50% of pts), regardless of relationship to study Tx, were fatigue, neutropenia and diarrhea. Grade ≥3 TEAEs reported in ≥50% pts were neutropenia (68%) and thrombocytopenia (50%). No pts have withdrawn or d/c Tx due to AEs. There was one grade 5 event, in a non-evaluable pt, related to a PE that occurred prior to DLT period. In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing was successful in all pts. At time of submission 20 of 28 (71%) were MRD - at 10-6. Conclusions: Interim results show that at the MTD the combination of V 400 mg daily, L 20 mg, with R is safe with a manageable toxicity profile and a high ORR and MRD - in pts with newly diagnosed MCL. Safety data is consistent with the AE profile noted for each drug without any unexpected or unique AEs. Updated results including BH3 profiling will be presented at the meeting. Clinical trial information: NCT03523975. [Table: see text]

Inhibition of Interleukin-6 (IL-6) Reverses Anemia In Patients with Advanced Non Small Cell Lung Cancer (NSCLC): Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 640-640 ◽  
Author(s):  
Michael W. Schuster ◽  
James R Rigas ◽  
Sergey V Orlov ◽  
Branislav Milovanovic ◽  
Kumar Prabhash ◽  
...  
Keyword(s):  
Adverse Events ◽  
Clinical Chemistry ◽  
Controlled Trial ◽  
Safety Data ◽  
Primary Objective ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Reactive Protein ◽  
Grade 3 ◽  
Cancer Related Anemia

Abstract Abstract 640 Background: ALD518 is a humanized, desialyated anti-IL-6 antibody being developed for the treatment of cancer-related anemia, cachexia and fatigue. The primary objective of the study was to determine the efficacy and safety of ALD518 in patients with advanced NSCLC. Secondary objectives examined hematologic parameters. Methods: 124 patients with NSCLC, ECOG 0–3, weight loss in the preceding 3 months of >5% body weight, hemoglobin (Hb) >7g/dL, and C-reactive protein (CRP) >10mg/L were dosed. Patients were randomized to 1 of 4 groups (n~30/group). Placebo or ALD518 80mg, 160mg, or 320mg was administered intravenously every 8 weeks. Pts were followed up for 24 weeks. Data included hematologic parameters, clinical chemistry, CRP, D-dimer, lean body mass and adverse events (AEs). Quality of life data included the FACIT-F, FACT-L, and FAACT questionnaires. Data presented in this abstract relates to the safety and hematology results. Results: 29 pts completed the study treatments and evaluations, 38 failed to complete every visit, 52 died of progressive disease, and 5 withdrew because of adverse events. There were no dose limiting toxicities (DLTs), infusion reactions, or anti-idiotypic antibody responses to ALD518 observed in the study. 84 pts had serious AEs of which 1 was deemed to be possibly related to administration of ALD518 (rectal hemorrhage). The majority of the serious adverse events were due to progression of the NSCLC. Six patients had a CTC grade 4 change in laboratory safety data during the study. Four patients experienced a grade 4 hypercalcemia: 1 (3.6%), 2 (6.1%), and 1 (3.2%) in the ALD518 80mg, 160mg and placebo groups, respectively, and there was 1 patient with grade 4 GGT elevation (placebo) and 1 patient with grade 4 hypokalemia (ALD518 160mg). There were no treatment related differences in vitals sign or 12-lead ECG data. The mean (±SD) values for Hb, hematocrit (Hct), mean corpuscular Hb (MCH) and platelet counts are listed below: 38/93 pts treated with ALD518 and 10/31 given placebo had a pre-dose Hb =< 11g/dL. 24 of these pts on ALD518 and 7 of these pts on placebo remained in the study at week 4. 14/24 pts on ALD518 and 0/7 on placebo had raised their Hb from =< 11g/dL to >= 12g/dL. Conclusions: ALD518 increased Hb, Hct, MCH in NSCLC pts and raised Hb to >= 12g/dL in 58% of pts with a Hb =< 11g/dL at baseline. There was also a modest fall in platelet count observed in patients treated with ALD518 but no patients had a CTC grade 4 thrombocytopenia and only one patient (ALD518 160mg group) had a grade 3 thrombocytopenia at one time point. There were no major safety signals related to the administration of ALD518. Further study of ALD518 as a novel non-erythropoietic stimulating agent for cancer-related anemia is warranted. Disclosures: Schuster: Alder Biopharmaceuticals Inc: Honoraria. Rigas: Alder Biopharmaceuticals inc: Honoraria. Smith:Alder Biopharmaceuticals Inc: Employment.

A Sequential Two-Stage Dose Escalation Study Evaluating The Safety and Efficacy Of Eltrombopag In Thrombocytopenic Patients With Myelodysplastic Syndrome (MDS) Resistant To Hypomethylating Agents (HMA)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2760-2760 ◽  
Author(s):  
Rami S Komrokji ◽  
Vu H. Duong ◽  
Ling Zhang ◽  
Ji-Hyun Lee ◽  
Eric Padron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Median Duration ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Duration Of Treatment ◽  
Dose Escalation Study ◽  
Grade 3

Abstract Introduction Thrombocytopenia remains a critical management challenge for MDS pts. The outcome of MDS Pts after HMA failure is poor. Eltrombopag is an oral, small non-peptide thormbopoeitin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We conducted an investigator initiated study with eltrombopag in MDS pts with thrombocytopenia after HMA failure. Methods The study is a phase 1, dose escalation design. Pts are allocated to dose cohorts of 50, 100, 150, 200, 250 and 300mg/day. Each dose cohort includes 6 pts. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. Pts must have at least one prior HMA treatment. The mean platelet count within a month of enrollment must be ≤ 50 X 109 /L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis ≥ grade 3, and prior TPO agonist use. The primary objective of the study is to determine the MTD. Dose-limiting toxicity (DLT) is defined as treatment related non-hematological grade 3-4 toxicity. If no DLTs were observed during the first 2 cycles of therapy, the next cohort of patients receives a higher dose of eltrombopag. Pts who did not receive treatment for 8 weeks were replaced for DLT assessment. The secondary endpoints include response, overall survival (OS) and leukemia free survival (LFS). Results Thirty-one pts were enrolled. Table-1 summarizes baseline characteristics. Most pts had higher risk MDS who were heavily pretreated. The median interval from MDS diagnosis was 28 months. Six pts were enrolled in cohort 1 (50 mg), 10 pts in cohort 2 (100 mg) (4 pts replaced (2 deaths unrelated to treatment, 1 infection, 1 progressive disease (PD)), 12 pts were enrolled in cohort 3 (150 mg) where 6 pts were replaced (5 PD and 1 infection), and to date, 3 pts are enrolled in cohort 4 (200 mg). No protocol defined DLT have been encountered to date. No grade 3 or 4 treatment related adverse events have been reported. The most common adverse events that were deemed possibly, or probably related to study drug included fatigue (n=9), diarrhea (n=6), night sweats (n=3), headache (n=3), numbness (n=3). There were 2 pts with grade 2 pneumonia and grade 3 fatigue, and 2 grade 2 diarrhea events. Seven pts (23%) developed leukocytosis on treatment and 13 pts (42%) experienced an increase in circulating myeloblasts at some point during study treatment. Three of 27 pts developed higher grade bone marrow myelofibrosis (change from grade 0-1 to grade 2-3), one of whom received the 50 mg dose and 2 pts on the150 mg dose. Eleven pts (35%) progressed to AML, 9 out of 11 patients who progressed had RAEB-2 or RAEB-t and 5 had poor risk cytogenetics. The median follow up duration is 23 months. The best response on study per IWG 2006 criteria include marrow CR (mCR) + Hematological improvement (HI) (6%, n=2), mCR (3%, n=1), HI (13%, n=4), stable disease (SD) (29%, n=9), PD (36%, n=11) and not evaluable for response (13%, n=4). The overall response rate (HI+) was 22% (7 out 31 pts) and 26% among pts evaluable for response (7 out of 27 pts). HI included 6 platelet responses and 1 erythroid response. Among 20 pts who were platelet transfusion dependent, 6 became transfusion independent (30%). The median duration of response was 3.3 months. The median duration of treatment is 2 months. The most common reasons for eltrombopag discontinuation were PD (48%) and infection (10%). Median OS was 5 months whereas median OS was 8 months among HI+ responders. The median LFS was 3.5 months. Conclusions Eltrombopag yielded modest responses in heavily treated higher risk MDS pts after HMA failure. Leukocytosis, increased circulating myeloblasts and myelofibrosis were observed in subsets of pts. Future development of eltrombopag as a single agent in MDS should be in lower risk MDS or in combination with HMA in higher risk MDS. Disclosures: Off Label Use: Use of eltrombopag in MDS.

Safety profile of avelumab in patients with advanced solid tumors: A JAVELIN pooled analysis of phase 1 and 2 data.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Karen Kelly ◽  
Jeffrey R. Infante ◽  
Matthew H. Taylor ◽  
Manish R. Patel ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Phase 1 ◽  
Safety Data ◽  
Pooled Analysis ◽  
Clinical Activity ◽  
Thyroid Disorder ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Grade 3

3059 Background: Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of avelumab. Methods: Patients (pts) received avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received ≥1 dose of avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = 295, 17%), and nausea (n = 150, 9%). 177 pts (10%) had a grade ≥3 TRAE; most common were fatigue and elevated lipase (17 [1%] each). TRAEs led to discontinuation in 107 pts (6%). Four pts (0.2%) died due to a TRAE. Any grade irAEs occurred in 247 pts (14%), which were grade ≥3 in 39 pts (2%) and considered serious in 43 pts (2%). The most common any grade irAEs were thyroid disorder (n = 98, 6%) and rash (n = 90, 5%). Other irAEs (eg, colitis, hepatitis, pneumonitis, adrenal insufficiency, myositis) each occurred in < 2%. irAEs led to discontinuation in 34 pts (2%). IRR or related symptoms (eg, chills, pyrexia, hypersensitivity) occurred in 439 pts (25%), which were grade 3 in 9 pts (0.5%) and grade 4 in 3 pts (0.2%). An IRR occurred at first infusion in 79% and within first 4 doses in 99%; 63/439 pts (14%) had IRR recurrence in later cycles. IRR led to dose interruption in 152 (9%), infusion rate reduction in 124 (7%), and discontinuation in 35 pts (2%). Conclusions: This large pooled analysis confirms that avelumab has an acceptable safety profile. A minority of pts experienced a grade ≥3 TRAE or irAE and discontinuation due to TRAEs was uncommon. IRRs mostly occurred at first infusion and the rate of recurrence was low. Clinical trial information: NCT01772004, NCT02155647.

CHOP-R (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, Rituximab) Compared to CPOP-R (Cyclophosphamide, Pixantrone, Vincristine, Prednisone, Rituxamib) in First-Line Therapy of Diffuse Large B Cell Lymphoma (DLBCL): An Interim Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3445-3445 ◽  
Author(s):  
Raoul Herbrecht ◽  
Stephen Couban ◽  
Florian Weissinger ◽  
Igor Gorbatchevsky ◽  
Richard H. van der Jagt
Keyword(s):  
Heart Failure ◽  
Adverse Events ◽  
Interim Analysis ◽  
Phase 1 ◽  
Safety Data ◽  
B Cell Lymphoma ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3

Abstract The CHOP-R regimen is the standard regimen for first-line therapy of patients with DLBCL. Pixantrone (BBR 2778) is a novel aza-anthracenedione with structural similarities to mitoxantrone. In a phase 1/2 study of CPOP in 65 patients with relapsed NHL who had received a first-line anthracycline-containing regimen, patients received pixantrone at 80–180 mg/m2. This study indicated substantial activity with an overall response rate of 77% and complete response (CR) rate of 54% with acceptable toxicity. Studies in indolent NHL demonstrated that the combination of pixantrone with rituximab is well tolerated and more active than rituximab alone (JCO, 24(18S), 2006:7578). To evaluate the safety and activity of CPOP-R with special regard to cardiac safety in the first-line setting, a randomized phase 2 study in untreated patients with DLBCL comparing CPOP-R to CHOP-R is being conducted. Patients with untreated, histologically confirmed CD20-positive DLBCL receive CHOP-R or CPOP-R every 21 days for 6–8 cycles. An interim analysis for efficacy was prospectively planned to be performed when 40 patients had completed 4 cycles of therapy to test whether the CR rate of CPOP-R (pixantrone dose of 150 mg/m2) is, with 95% confidence, not more than 15% less than the CR rate of CHOP-R. We report the results of this analysis, which included 40 patients (21 CPOP-R and 19 CHOP-R) who had completed 4 cycles or had prematurely withdrawn from the study. Preliminary safety data (CPOP-R=27 patients, CHOP-R=30 patients) were also evaluated. CR rates after 4 cycles based on investigators’assessment were similar between arms (CPOP-R=33%, CHOP-R=37%). In general, adverse events were equal between arms. There were no more grade 3–4 adverse events (41% CPOP-R vs 50% CHOP-R) and no more grade 3–4 treatment-related adverse events (33% in CPOP-R vs 40% in CHOP-R) in the CPOP-R arm compared to the CHOP-R arm. 8 patients in each arm had asymptomatic absolute LVEF declines of ≥10%. 3 patients in the CPOP-R arm had a LVEF decline of >15% and ≤20% compared to 5 patients in the CHOP-R arm. No patients in the CPOP-R arm had a >20% LVEF decline compared to 2 patients in the CHOP-R arm. No heart failure or deaths resulting from heart failure have been reported. Infections reported as serious adverse events occurred in 1 patient (4%) in the CPOP-R arm and 3 patients (10%) in the CHOP-R arm. Grade 3–4 neutropenia was similar (CPOP-R = 34%, CHOP-R = 30%). Febrile neutropenia was less frequent in the CPOP-R arm (4% vs 23%). There were 2 deaths within 30 days of the last dose of study drug on CPOP-R arm. Both patients were > 80 years; 1 of the events was attributed to study treatment secondary to neutropenic infection. No deaths were reported in the CHOP-R arm. Based on this preliminary analysis, we conclude that for 1st-line therapy of patients with DLBCL, CPOP-R has similar activity to CHOP-R with no more toxicity. Further follow-up is required.

scholarly journals Design of the ACcomplisH Trial: A Phase 2, Multicenter, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Weekly TransCon CNP in Children With Achondroplasia

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A712-A713
Author(s):  
Ravi Savririyan ◽  
Yuri Zarate ◽  
Janet M Legare ◽  
Carl Decker ◽  
Adebola Giwa ◽  
...  
Keyword(s):  
Clinical Laboratory ◽  
Phase 1 ◽  
Safety Data ◽  
Data Monitoring Committee ◽  
Primary Objective ◽  
Height Velocity ◽  
Weekly Dose ◽  
Phase 2 ◽  
Dose Cohort ◽  
Safety And Efficacy

Abstract Background: Achondroplasia (ACH) is the most common skeletal dysplasia and the most frequent form of dwarfism. ACH is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene and results in impairment of the endochondral ossification processes. C-type natriuretic peptide (CNP) promotes chondrocyte development through inhibition of the FGFR3 pathway, specifically through activation of NPRB. CNP is a desirable target as it is known to increase chondrocyte development without off-target effects (Bocciardi, 2007). TransCon CNP is a long-acting prodrug of CNP designed to optimize safety and efficacy with a once-weekly dose. The Phase 1 clinical trial with TransCon CNP demonstrated that doses up to 150 μg CNP/kg were well-tolerated in healthy adult male volunteers, with no clinically significant trends observed in clinical laboratory assessments, vital sign measurements, ECG parameters, or physical examination findings. Methods: The phase 2 ACcomplisH trial will be conducted at over 35 sites worldwide. The primary objective of the trial will be to evaluate the safety and efficacy of once-weekly TransCon CNP compared to placebo at 12 months in prepubertal children, aged 2-10 years old, with ACH. Approximately 60 subjects will be randomized 3:1 to receive either weekly TransCon CNP or placebo. Following screening and verification of clinical ACH with genetic confirmation, subjects will remain within the dose cohort for 52 weeks of treatment. TransCon CNP will be dosed 6 to 100 μg CNP/kg/week across 4 cohorts, with an optional 5th cohort at up to 200 μg CNP/kg/week. An independent Data Monitoring Committee will review safety data prior to initiation of a higher dose cohort. The primary endpoint will evaluate annualized height velocity at 52 weeks of TransCon CNP or placebo. Key secondary endpoints will examine change in upper to lower body segment ratio at week 52, safety, pharmacokinetics (PK), and quality of life associated with weekly TransCon CNP. Conclusion: CNP is targeted specifically to the underlying pathology of ACH through inhibition FGFR3. No effective medicinal product is currently available for the treatment of ACH. TransCon CNP is designed to provide sustained exposure of CNP. This ongoing Phase 2 ACcomplisH trial is designed to assess the efficacy, safety, and PK of TransCon CNP by weekly administration compared to placebo.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

ANCHOR (OP-104): Melflufen plus dexamethasone (dex) and bortezomib (BTZ) in relapsed/refractory multiple myeloma (RRMM)—Optimal dose, updated efficacy and safety results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8037-8037
Author(s):  
Roman Hajek ◽  
Luděk Pour ◽  
Miquel Granell ◽  
Vladimir Maisnar ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Partial Response ◽  
Cardiac Failure ◽  
Alkylating Agents ◽  
Phase 1 ◽  
Optimal Dose ◽  
Complete Response ◽  
Primary Objective ◽  
Clinical Activity ◽  
Development Of Resistance ◽  
Grade 3

8037 Background: Development of resistance to standard treatments for RRMM highlights the need for novel therapies. Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen + dex showed clinical activity and an acceptable safety profile in HORIZON (Richardson et al. J Clin Oncol. 2020 Dec 9 [Epub]). This is an update of the BTZ arm of the phase 1/2a ANCHOR study (NCT03481556). Methods: Patients (pts) with RRMM were intolerant or refractory to a prior IMiD, with 1-4 prior lines of therapy (LoTs). Prior treatment with a proteasome inhibitor (PI) was allowed, but pts could not be refractory to PIs in the last LoT. Melflufen (30, 40, or 20 mg intravenously; d 1 of each 28-d cycle) was administered with BTZ (1.3 mg/m2 subcutaneous) + oral dex (20 mg on d 1, 4, 8, and 11 and 40 mg on d 15 and 22; dex dose reduced if aged ≥ 75 y). The primary objective in phase 1 was to determine the optimal phase 2 dose of melflufen for this combination. Results: As of the data cutoff date (October 19, 2020), 13 pts received melflufen (30 mg, n = 6; 40 mg, n = 7) + dex and BTZ. In the 30 mg and 40 mg cohorts, respectively, median age was 78.5 y (range, 70-82) and 70.0 y (range, 61-76); median prior LoTs was 3.5 (range, 2-4) and 2.0 (range, 1-4); 33% and 50% of evaluable pts had high-risk cytogenetics; 83% and 71% were refractory to last LoT; 100% and 86% received a prior PI; 33% and 14% were refractory to PIs. In the 30 mg and 40 mg cohorts, respectively, median treatment duration was 6.5 mo (range, 1.4-29.0) and 8.7 mo (range, 2.1-19.6); 4 (67%) and 4 pts (57%) were still on treatment; 2 and 3 pts discontinued (30 mg: progressive disease [PD] and other [1 pt each]; 40 mg: adverse event [AE], lack of efficacy, and PD [1 pt each]). Confirmed overall response rate in the 30 mg and 40 mg cohorts, respectively, was 50% (1 very good partial response [VGPR] and 2 partial response [PR]) and 71% (1 complete response, 3 VGPR, and 1 PR). Most common grade 3/4 treatment-related AEs (TRAEs) were thrombocytopenia (30 mg: 50%; 40 mg: 100%) and neutropenia (30 mg: 33%; 40 mg: 71%); grade 3/4 nonhematologic TRAEs were infrequent; 3 pts discontinued study treatment due to treatment-emergent AEs (30 mg: cardiac failure chronic and osteolysis [1 pt each]; 40 mg: thrombocytopenia [1 pt]). Serious TRAEs occurred in 2 pts (33%) in the 30 mg cohort (neutropenia and pneumonia [1 pt], syncope [1 pt]) and 1 pt (14%) in the 40 mg cohort (thrombocytopenia and neutropenia). No dose-limiting toxicities occurred at either dose level. Fatal AEs occurred in 1 pt in the 30 mg cohort (cardiac failure chronic; unrelated to study treatment). Conclusions: ANCHOR determined that the optimal dose of melflufen is 30 mg + dex and BTZ; results showed clinical activity in heavily pretreated pts. Recruitment is ongoing; updated data will be presented. Clinical trial information: NCT03481556.

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.

CheckMate 8KX: Phase 1/2 multitumor preliminary analyses of a subcutaneous formulation of nivolumab (± rHuPH20).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2575-2575
Author(s):  
Sara Lonardi ◽  
Iwona Lugowska ◽  
Christopher G. C. A. Jackson ◽  
Anne O'Donnell ◽  
Rastilav Bahleda ◽  
...  
Keyword(s):  
De Novo ◽  
Phase 1 ◽  
Geometric Mean ◽  
Primary Objective ◽  
Tumor Type ◽  
Part D ◽  
Part C ◽  
Local Site ◽  
Survival Expectations ◽  
Grade 3

2575 Background: Immunotherapy has transformed cancer survival expectations. Nivolumab (NIVO), a programmed death-1 inhibitor, is approved for intravenous (IV) administration across multiple cancers. BMS is developing a subcutaneous (SC) NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), to allow for more rapid delivery and the potential to decrease treatment burden. We report the first data on pharmacokinetics (PK), pharmacodynamics, safety, and immunogenicity for SC NIVO + rHuPH20. Methods: CheckMate 8KX is a phase 1/2 study in checkpoint inhibitor-naïve patients (pts) who were ≥ 18 years of age, ECOG PS 0–1, with metastatic/unresectable solid tumors and measurable disease. The primary objective was to describe SC NIVO PK; secondary objectives were safety and immunogenicity. Additional analyses compared exposures to historical IV NIVO (Zhao X, et al. J Clin Oncol 2020;31:302–309). In cycle 1, pts in Part A received SC NIVO 720 mg + rHuPH20, and pts in Part B received SC NIVO 720 mg, SC NIVO 960 mg + rHuPH20, or SC NIVO 960 mg. For cycles 2+, pts in Parts A and B received IV NIVO 480 mg every 4 weeks (Q4W). Pts still on study switched to Part C, SC NIVO 1200 mg + rHuPH20 until end of therapy. In Part D, pts received de novo SC NIVO 1200 mg + rHuPH20 Q4W. Results: Patient characteristics varied by age, weight, tumor type, and prior treatment. NIVO exposures increased with increasing SC dose (Table). For 960 mg and 1200 mg NIVO + rHuPH20, Cavg and Ctau were above geometric mean exposures for IV NIVO 3 mg/kg every 2 weeks (Q2W), and Cmax was below IV NIVO 10 mg/kg Q2W. In Part C (n = 28), 13 (46.4%) pts experienced any-grade TRAEs with no new/worsening grade 3+ TRAEs or TRAEs leading to discontinuation/death; 7 (25.0%) reported grade 1 local site reactions. In Part D (n = 36), 27 (75.0%) pts experienced any-grade TRAEs, 4 (11.1%) grade 3/4 TRAEs, 2 (5.6%) serious grade 3/4 TRAEs with 1 leading to discontinuation, and no treatment-related deaths; 10 (27.8%) reported grade 1 local site reactions. Anti-NIVO antibodies (Ab) were observed with SC NIVO but not associated with altered PK/safety, or neutralizing Ab. Exploratory biomarker data found increased CD8+ tumor-infiltrating lymphocytes and PD-L1 tumor expression in post-treatment biopsies, similar to IV NIVO. Conclusions: Exposures associated with SC NIVO + rHuPH20 doses investigated in CheckMate 8KX were well tolerated, with a safety profile consistent with IV NIVO. Data support evaluation of SC NIVO + rHuPH20 in a phase 3 study. Clinical trial information: NCT03656718. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document