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.

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.

scholarly journals A phase 1 and randomized controlled phase 2 trial of the safety and efficacy of the combination of gemcitabine and docetaxel with ontuxizumab (MORAb‐004) in metastatic soft‐tissue sarcomas

Cancer ◽  
2019 ◽  
Vol 125 (14) ◽  
pp. 2445-2454 ◽  
Author(s):  
Robin L. Jones ◽  
Sant P. Chawla ◽  
Steven Attia ◽  
Patrick Schöffski ◽  
Hans Gelderblom ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase 1 ◽  
Soft Tissue Sarcomas ◽  
Phase 2 ◽  
Safety And Efficacy ◽  
Randomized Controlled ◽  
Phase 2 Trial

scholarly journals Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study

2021 ◽  
Author(s):  
Takeshi Kato ◽  
Yoshinori Kagawa ◽  
Yasutoshi Kuboki ◽  
Makio Gamoh ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Therapeutic Option ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Wild Type ◽  
Open Label ◽  
Safety And Efficacy ◽  
Multicentre Phase

Abstract Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

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]

A phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE): Results of the phase 1 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17020-e17020
Author(s):  
Rana R. McKay ◽  
Wanling Xie ◽  
Archana Ajmera ◽  
Biren Saraiya ◽  
Mamta Parikh ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Bone Metastases ◽  
Phase 1 ◽  
Safety Data ◽  
Fixed Dose ◽  
Phase 2 ◽  
Evaluation Period ◽  
Radium 223 ◽  
Psa Response ◽  
Dose Reductions

e17020 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has improved survival in mCRPC. In preclinical models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the hypothesis that radium-223 + olaparib will demonstrate anti-tumor activity in mCRPC irrespective of homologous recombination repair deficiency (HRD) status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of radium-223 + olaparib. Eligible patients (pts) had mCRPC with ≥2 bone metastases without visceral metastases or lymphadenopathy > 4 cm. There was no limit on prior therapy. All pts had a baseline biopsy. The phase 1 used a 3+3 dose escalation design with fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). Dose level 1 (DL1) was olaparib 200 mg PO BID; DL2 was olaparib 300 mg PO BID. The primary objective was to determine the recommended phase 2 dose (RP2D) and safety. The dose limiting toxicities (DLT) evaluation period was 2 cycles (1 cycle=28 days). Secondary endpoints included radiographic progression-free survival (rPFS) defined by PCWG3 criteria, PSA response (50% decline from baseline), and alkaline phosphatase response (30% decline from baseline). Results: 12 pts were enrolled on the phase 1. Median age was 68 (range 59-81) years. Median prior lines of CRPC therapies was 2 (1-5), including 3 (25%) who had received prior chemotherapy and 100% a prior novel hormone therapy. 6 pts were enrolled at DL1. 1 patient experienced a DLT outside the DLT evaluation period. 3 pts had grade (G) 3-4 treatment-related adverse events (TrAE) including G3 anemia (n=2) and G3 thrombocytopenia (n=1). No patient underwent dose reductions at DL1. 6 pts were enrolled at DL2. 1 patient experienced a DLT outside the DLT evaluation period. 2 pts had G3-4 TrAE including G3 anemia and G4 lymphocytopenia (n=1) and G3 stroke (n=1). 5 underwent dose reductions at DL2. There were no G5 events. Reason for treatment discontinuation is in the table below. After review of safety data, the safety monitoring committee deemed the RP2D of olaparib at 200 mg BID when combined with radium-223. Overall, PSA response and alkaline phosphatase response were 16.7% (n=2, 1 at DL1, 1 at DL2) and 67% (n=8, 3 at DL1, 5 at DL2), respectively. Median follow-up was 6.5 (range 2.8, 11.8) months, and 6-month rPFS was 57% (95% CI: 25%, 80%). Conclusions: We demonstrate that olaparib can be safety combined with radium-223 with RP2 dose of 200 mg BID. The phase 2 study of radium-223 +/- olaparib is accruing (target 120 pts). Outcomes by HRD status will be presented. Clinical trial information: NCT03317392. [Table: see text]

scholarly journals P219 Long-term safety of filgotinib in patients with PsA: week 52 safety data from a Phase 2 open-label extension study

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Laura Coates ◽  
Philip Mease ◽  
Dafna Gladman ◽  
Filip Van den Bosch ◽  
Anna Rychlewska-Hanczewska ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Safety Data ◽  
Janus Kinase ◽  
Controlled Study ◽  
Stock Ownership ◽  
Phase 2 ◽  
Open Label ◽  
Safety And Efficacy ◽  
Open Label Extension

Abstract Background Filgotinib (FIL) is an orally administered, selective janus kinase 1 (JAK1) inhibitor in development for psoriatic arthritis (PsA). Efficacy and safety of FIL in patients with active PsA were evaluated in a 16-week phase 2 study (EQUATOR, NCT03101670). After 16 weeks, patients could roll-over to an Open Label Extension (OLE) Study (EQUATOR2, NCT03320876) for the purpose of evaluating long-term safety and efficacy. The aim of this analysis was to assess safety and efficacy through 52 weeks of exposure to filgotinib. Methods Patients who completed the randomised, double-blind, placebo-controlled study were eligible for participation in the OLE, during which all patients received once daily (qd) open-label FIL 200mg. In this interim analysis of OLE, for the safety analysis, all data were included from the screening in the core study up to the data cut of 18 April 2019 in the OLE. For the efficacy analysis, all data until OLE Week 52 visit for each patient were included (observed case analysis). Results Of the 131 patients randomised and dosed in EQUATOR, 124 (95%) completed the study and 122 (93%) enrolled in EQUATOR2; 50% were female and mean age was 50. At this interim analysis, 106/122 (87%) remained in the OLE (premature discontinuations during OLE due to: 4 for safety, 11 withdrew consent, and 1 for other reasons). Cumulative patient years of exposure (PYE) on FIL were 160, median time on FIL was 66 weeks. Key safety data are summarised in Table 1. Key ≥Grade 2 treatment-emergent laboratory abnormalities seen with FIL arm (N = 128) compared with PBO (N = 66) were lymphocyte decrease 11.1% vs 4.5%, neutrophil decrease 5.5% vs 0%, ALT increase 1.6% vs 1.5% and creatinine increase 0.8% vs 0%, respectively. At week 52, 34% of the patients fulfilled criteria for minimal disease activity and 81%, 55%, and 33% of patients, respectively, achieved ACR20/50/70 responses. Conclusion FIL 200mg qd was generally well tolerated and the safety profile in PsA was comparable to that observed in the FIL rheumatoid arthritis studies. The data from this interim analysis suggest that further improvement of the patient condition can be expected beyond 16 weeks of treatment. Disclosures L. Coates: Other; Received support from Abbvie, Amgen, Celgene, Galapagos, Janssen, Lilly, Novartis, Pfizer, Prothena, Sun pharma, and UCB. P. Mease: Other; Received support from Abbvie, Amgen, BMS, Celgene, Galapagos, Genentech, Gilead, Janssen, Eli Lilly, Merck, Novartis, Pfizer, SUN, and UCB. D. Gladman: Other; Received support from Abbvie, Amgen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, UCB, BMS, and Galapagos. F. Van den Bosch: Other; Received support from Abbvie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer, and UCB. A. Rychlewska-Hanczewska: Other; Received support from Galapagos and Gilead Sciences. C. Tasset: Corporate appointments; Employee of Galapagos NV. L. Meuleners: Corporate appointments; Employee of Galapagos NV. M. Trivedi: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. Y. Guo: Corporate appointments; Employee of Gilead Sciences, Inc... Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R. Besuyen: Other; Employee of Galapagos NV. P. Helliwell: Other; Received support from Abbvie, Amgen, Celgene, Galapagos, Janssen, Novartis, Pfizer, and UCB.

Primary analysis of phase 2 results of cemiplimab, a human monoclonal anti-PD-1, in patients (pts) with locally advanced cutaneous squamous cell carcinoma (laCSCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6015-6015 ◽  
Author(s):  
Michael Robert Migden ◽  
Nikhil I. Khushalani ◽  
Anne Lynn S. Chang ◽  
Danny Rischin ◽  
Chrysalyne D. Schmults ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Median Duration ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Phase 2 ◽  
Primary Analysis ◽  
Curative Surgery ◽  
Grade 3

6015 Background: Cemiplimab (REGN2810) produced substantial antitumor activity with durable responses in Phase 1 CSCC expansion cohorts and Phase 2 metastatic (m) CSCC cohort. We now present the primary analysis of the Phase 2 laCSCC cohort (NCT02760498; data cutoff date: Oct 10, 2018). Methods: Pts with laCSCC received cemiplimab 3 mg/kg IV every 2 weeks (Q2W). Tumor measurements were performed Q8W. The primary objective was to evaluate objective response rate (ORR; complete response [CR] + partial response [PR]) according to independent central review (per RECIST 1.1 for scans; modified WHO criteria for photos). Results: 78 pts were enrolled (59 M/ 19 F; median age: 74 years; ECOG PS: 0 in 38 pts, 1 in 40 pts; primary CSCC site: head/neck in 79.5%; prior systemic therapy: 15.4%; prior radiotherapy: 55.1%). Median duration of follow-up was 9.3 months (range: 0.8–27.9). ORR by central review was 43.6% (95% CI: 32.4–55.3; 10 CRs and 24 PRs); investigator-assessed (INV) ORR was 52.6% (95% CI: 40.9–64.0; 13 CRs and 28 PRs). Median duration of response (DOR) has not been reached. The longest DOR at data cut-off was 24.2 months and was still ongoing. Durable disease control rate (stable disease or response for ≥16 weeks) was 62.8% (95% CI: 51.1–73.5). Median observed time to response was 1.9 months (range: 1.8–8.8). Median progression-free and overall survival have not been reached. Tumor PD-L1 status is available for 48/78 pts, tumor mutational burden analysis (from targeted exome panel) is ongoing for ≥40/78 pts; response correlation analyses are planned. The most common treatment-emergent adverse events (AEs; all grades, Grade ≥3) were fatigue (42.3%, 1.3%), diarrhea and pruritus (both 26.9%, 0%), and nausea (21.8%, 0%). INV grade ≥3 immune-related AEs occurred in 10.3% of pts. One pt died due to an unknown cause that was assessed as treatment-related. Conclusions: Cemiplimab 3 mg/kg Q2W showed substantial antitumor activity, durable responses, and acceptable safety profile in pts with laCSCC. These data strongly support the recent FDA approval of cemiplimab-rwlc for pts with mCSCC or laCSCC who are not candidates for curative surgery or curative radiation. Clinical trial information: NCT02760498.

Initial results of a phase III investigation of safety/efficacy of nivolumab and ABI-009 (nab-sirolimus) in advanced undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), chondrosarcoma (CS), osteosarcoma (OS), and Ewing sarcoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 21-21
Author(s):  
Victoria S. Chua-Alcala ◽  
Katherine Kim ◽  
Nupur Assudani ◽  
Ahmad Al-Shihabi ◽  
Doris Quon ◽  
...  
Keyword(s):  
Ewing Sarcoma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Dose Finding ◽  
Phase Iii ◽  
Phase 2 ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma ◽  
Grade 3

21 Background: Objectives: (1) To investigate the MTD of ABI-009 when given with nivolumab, a PD-1 inhibitor, in previously treated advanced undifferentiated pleomorphic sarcoma, liposarcoma, chondrosarcoma, osteosarcoma and Ewing sarcoma; (2) To investigate the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of this combination therapy in the above mentioned patient group, and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: This is an IRB approved protocol with 2 parts. The Phase 1 part is a dose-finding study using the “cohort of three design”, wherein standard doses of nivolumab 240 mg is given iv every 3 weeks (Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75, and 100 mg/m2. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: The Phase 1 part of study is closed, after 9 patients were treated successfully at 3 dose levels. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1 (n=3): Grade 3 treatment-related adverse events (TRAEs) included hyperdyslipidemia (n=1), and hyperglycemia (n=1). At Dose 2 (n=3): Grade 3 TRAEs included increased ALT (n=1). At Dose 3 (n=3): Grade 3 TRAEs included hypophosphatemia (n=1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. Conclusions: The primary objective has been met with no DLTs, the MTD was not reached and Dose 3 has been designated as the phase 2 dose of ABI-009 which is on-going. Clinical trial information: NCT03190174.

Masterkey-01: Phase I/II, open-label multicenter study to assess safety, tolerability, pharmacokinetics, and antitumor activity of BDTX-189, an inhibitor of allosteric ErbB mutations, in patients with advanced solid malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3665-TPS3665
Author(s):  
Erika Paige Hamilton ◽  
Manish R. Patel ◽  
Jordi Rodon ◽  
David S. Hong ◽  
Alison M. Schram ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Standard Therapy ◽  
Drug Exposure ◽  
Locally Advanced ◽  
Safety Data ◽  
Unmet Need ◽  
Primary Objective ◽  
Insertion Mutation ◽  
Phase 2 ◽  
Exon 20

TPS3665 Background: A significant unmet need exists for drugs targeting allosteric ErbB mutations (non-canonical mutations outside the ATP binding site). Current EGFR and HER2 tyrosine kinase inhibitors or mAbs have limited antitumor activity against allosteric mutations, resulting in toxicity before adequate drug exposure (Connell and Doherty, 2017). BDTX-189 is a potent and selective orally available irreversible inhibitor targeting unique oncogenic driver mutations of ErbB kinases in EGFR and HER2, while sparing WT EGFR. Preclinical studies demonstrated antitumor activity across a range of allosteric ErbB mutants, including extracellular domain allosteric mutations of HER2 as well as EGFR and HER2 kinase domain exon 20 insertions (Buck, 2019). This first-in-human trial (NCT04209465) is aimed to determine the recommended phase 2 dose (RP2) and schedule (Phase 1, P1), and evaluate the efficacy (Phase 2, P2) of BDTX-189. P1 primary objective is to determine the RP2 dose and schedule of monotherapy BDTX-189. Secondary objectives include assessment of safety, tolerability, pharmacokinetics (PK), pharmacodynamic (PD) effects in tumor, and preliminary efficacy. The P2 primary objective is to assess antitumor activity of monotherapy BDTX-189. Methods: The study will enroll patients (pts) ≥18 yrs with histologically or cytologically confirmed locally advanced or metastatic solid tumors with no standard therapy available or for whom standard therapy is unsuitable or intolerable. P1 dose-escalation will use a BOIN design (Yuan, 2016) and will enroll ≤ 88 pts with allosteric HER2 or HER3 mutation; EGFR or HER2 exon 20 insertion mutation; HER2 amplified or overexpressing tumor; or EGFR exon 19 deletion or L858R mutation. BDTX-189 will be dosed orally (PO) initially QD in 3 wk cycles. Regimen optimization will use PK, PD and safety data and may explore a BID schedule. An expansion cohort of ≤12 pts will further evaluate safety and preliminary efficacy of BDTX-189 prior to P2. P2, utilizing a Simon 2-stage design, will enroll ≤100 pts with NSCLC with EGFR or HER2 exon 20 insertion mutations (cohort 1); breast cancer with an allosteric ErbB mutation (cohort 2); tumors (except breast) with S310F/Y mutation (cohort 3); and other allosteric ErbB mutations not defined in cohorts 1-3 (cohort 4). Assessments include safety, tolerability, DLTs, evaluation of MTD, PK, PD, and preliminary antitumor activity. Enrollment began 1/2020. Clinical trial information: NCT04209465 .

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