MM-003: A phase III, multicenter, randomized, open-label study of pomalidomide (POM) plus low-dose dexamethasone (LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8510-8510 ◽  
Author(s):  
Jesùs F. San-Miguel ◽  
Katja C. Weisel ◽  
Philippe Moreau ◽  
Martha Lacy ◽  
Kevin W. Song ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Median Number ◽  
Phase Iii ◽  
High Dose ◽  
Open Label ◽  
High Dose Dexamethasone ◽  
Intent To Treat

8510 Background: RRMM patients (pts) who have exhausted treatment (Tx) with bortezomib (BORT) and lenalidomide (LEN) or thalidomide have a poor prognosis with short overall survival (OS). HiDEX is a well-established standard Tx in RRMM. POM has demonstrated clinical efficacy in pts refractory to LEN and BORT. MM-003 compared POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT and who progressed on their last Tx. Methods: Pts must have been refractory to last prior Tx (progressive disease [PD] during Tx or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Pts were randomized 2:1 to receive 28-day cycles of POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20. Tx continued until PD or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS, overall response rate (ORR; ≥ partial response), and safety. Analyses were based on intent to treat. Results: 455 pts were randomized to POM + LoDEX (n = 302) or HiDEX (n = 153). The median number of prior Tx was 5 (range 1-17). 72% were refractory to LEN and BORT. Median follow-up was 4 months. POM + LoDEX significantly extended median PFS (3.6 vs. 1.8 months, HR = 0.45, P < .001) and OS (not reached vs. 7.8 months, HR = 0.53, P < .001) vs. HiDEX. The OS benefit was observed despite 29% of HiDEX pts receiving POM after PD. The trial met the primary endpoint of PFS, crossed the upper boundary for OS superiority, and the Data Monitoring Committee recommended crossover from HiDEX to POM ± DEX. With updated data, the ORR was 21% for POM + LoDEX vs. 3% for HiDEX (P < .001) and 24% vs 3% for pts randomized ≥ 6 months post-enrollment (P < .001). The most frequent grade 3/4 adverse events (AEs) for POM + LoDEX vs. HiDEX were neutropenia (42% vs. 15%), anemia (27% vs. 29%), and infection (24% vs. 23%). Discontinuation due to AEs was infrequent (7% vs. 6%). Updated data will be presented. Conclusions: POM + LoDEX significantly extended PFS and OS vs. HiDEX in pts who failed LEN and BORT. POM + LoDEX should become a standard of care in RRMM pts who have exhausted Tx with LEN and BORT. Clinical trial information: NCT01311687.

Pomalidomide plus low-dose dexamethasone (POM + LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM): Impact of cytogenetics in MM-003.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8528-8528
Author(s):  
Hartmut Goldschmidt ◽  
Meletios A. Dimopoulos ◽  
Katja C. Weisel ◽  
Philippe Moreau ◽  
Martha Lacy ◽  
...  
Keyword(s):  
High Risk ◽  
Progression Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Open Label ◽  
High Dose Dexamethasone ◽  
Common Grade ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Intent To Treat

8528 Background: RRMM patients (pts) who fail lenalidomide (LEN) and bortezomib (BORT) have poor prognosis. High-risk cytogenetics predict shorter survival. POM + LoDEX has demonstrated efficacy in pts with prior LEN and BORT and high-risk cytogenetics. MM-003 is an open-label, multicenter, phase III trial comparing POM + LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT treatment (Tx) and have progressed on their last therapy. Methods: Pts must have been refractory to the last prior Tx (progressive disease [PD] during or within 60 days) and failed LEN and BORT after ≥ 2 consecutive cycles of each (alone or in combination). Randomization was 2:1 to POM 4 mg D1–21 + DEX 40 mg (20 mg for pts aged > 75 y) weekly; or DEX 40 mg (20 mg for pts aged > 75 y) D1–4, 9–12, and 17–20 (28-day cycles). Tx continued until PD or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS and AEs. This analysis examined pts meeting modified high-risk cytogenetic criteria—del(17p13) and/or t(4p16/14q32). Results: 302 pts received POM + LoDEX, and 153 pts received HiDEX. 225 and 107 pts, respectively, were evaluable for cytogenetics. Baseline characteristics were similar. Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX, regardless of cytogenetic risk (Table). The most common grade 3/4 AEs were neutropenia, anemia, and infection (Table). Discontinuation due to AE was low: 4% vs. 6% (high risk) and 10% vs. 4% (standard risk). Conclusions: Median PFS and OS were significantly longer with POM + LoDEX vs. HiDEX in pts with cytogenetically-defined high-risk disease, consistent with results from the intent-to-treat population. Tolerability was acceptable. POM + LoDEX should be considered a new Tx option in pts failing LEN and BORT. Clinical trial information: NCT01311687. [Table: see text]

Randomized phase III trial of regorafenib in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) progressing despite prior treatment with at least imatinib (IM) and sunitinib (SU): GRID trial.

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA10008-LBA10008 ◽  
Author(s):  
George D. Demetri ◽  
Peter Reichardt ◽  
Yoon-Koo Kang ◽  
Jean-Yves Blay ◽  
Heikki Joensuu ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Double Blind Study ◽  
Open Label ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Multikinase Inhibitor

LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placebo (PL). The primary endpoint was progression-free survival (PFS) (modified RECIST 1.1, independent central review). Secondary endpoints included overall survival (OS), disease control rate (DCR, defined as rate of partial response [PR] plus stable disease [SD] lasting for ≥12 wks), response rate and duration, safety and correlative genotype analyses. At time of PD, pts were eligible for unblinding and crossover to open-label REG. Results: Between Jan and Aug of 2011, 234 pts were screened; 199 were randomized (REG: 133, PL: 66). Pts were stratified at randomization according to number of prior systemic therapies and geographical region. Baseline characteristics were balanced between the two arms. The primary endpoint was met: median PFS was 4.8 months for REG vs. 0.9 months for PL. Hazard ratio for PFS was 0.27 (95% CI, 0.18-0.39), p<0.0001. PFS rates at 3 and 6 months were 60% and 38% for REG vs. 11% and 0% for PL. DCR was 53% (REG) vs. 9% (PL).The HR for OS was 0.77 (p=0.20) with 85% PL pts having crossed over to REG. The most common > grade 3 treatment-emergent AEs in the REG arm during double-blind study were hypertension (28%), hand-foot skin reaction (21%), and diarrhea (8%). Conclusions: This randomized trial demonstrated that REG significantly improved PFS and DCR in pts with advanced GIST after failure of at least prior IM and SU. REG was well tolerated, with AEs as expected for this class and manageable with dose modifications.

Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8588-8588 ◽  
Author(s):  
David Samuel DiCapua Siegel ◽  
Paul Gerard Guy Richardson ◽  
Ravi Vij ◽  
Craig C. Hofmeister ◽  
Rachid C. Baz ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Progression Free Survival ◽  
Response Duration ◽  
Median Number ◽  
Open Label ◽  
Safety And Efficacy ◽  
Vein Thrombosis ◽  
Intent To Treat

8588 Background: MM-002 is a randomized, open-label, multicenter phase II trial evaluating the safety and efficacy of POM with or without LoDEX in advanced RRMM pts. Methods: Pts who had received ≥ 2 prior therapies, including lenalidomide (LEN) and bortezomib (BORT), and were refractory to their last treatment were randomized to POM+LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (according to EBMT criteria and investigator assessment), response duration, overall survival (OS), and safety. The efficacy outcomes are based on the intent-to-treat population (POM+LoDEX, n = 113; POM, n = 108). Results: The median number of prior therapies in each group was 5 (range 1–13). In the POM+LoDEX arm, 30 (27%) pts had high-risk cytogenetics, including del(17p13) and/or t(4p16/14q32). The overall response rate (≥ partial response) was 34% and 15% with POM+LoDEX and POM, respectively, with a median duration of 8.3 (95% CI: 5.8–10.1) and 8.8 (95% CI: 5.5–11.4) mos, respectively. At least minimal response was observed in 45% and 31% of pts, respectively. Median PFS was 4.6 (95% CI: 3.6–5.5) and 2.6 (95% CI: 1.9–2.8) mos with POM+LoDEX and POM, respectively, with a median follow-up of 16.0 and 12.2 mos. Median OS was 16.5 (95% CI: 12.4–18.5) and 13.6 (95% CI: 9.6–18.1) mos, respectively. The most common treatment emergent Gr 3/4 adverse events (AEs) reported in the safety population (n = 219) were neutropenia (44%), anemia (23%), thrombocytopenia (21%), and pneumonia (18%); there were no reports of Gr 3/4 peripheral neuropathy. The incidence of deep-vein thrombosis was low (2%). AEs were managed through dose reductions or interruptions, and supportive care with G-CSF (52%), RBC transfusions (47%), and platelet transfusions (17%). Discontinuations due to AEs were 10%. Conclusions: POM with or without LoDEX is clinically effective and generally well tolerated in RRMM pts who have received multiple prior treatments, including LEN and BORT. AEs were predictable and manageable. Updated data will be presented at the meeting. Clinical trial information: NCT00833833.

DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8556-TPS8556 ◽  
Author(s):  
Saad Zafar Usmani ◽  
Evangelos Terpos ◽  
Wojt Janowski ◽  
Hang Quach ◽  
Sarah West ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Phase Iii ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Open Label

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

Everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET): Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 158-158 ◽  
Author(s):  
M. H. Shah ◽  
T. Ito ◽  
C. Lombard-Bohas ◽  
E. M. Wolin ◽  
E. Van Cutsem ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Controlled Trial ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Phase Ii Studies ◽  
The Impact ◽  
Patient Subgroups

158 Background: There is an unmet medical need for effective treatments for patients with advanced pNET. Systemic therapies for advanced pNET are limited both by toxicity and efficacy. Everolimus, an oral mTOR inhibitor, has shown promising antitumor activity in 2 phase II studies, leading to further investigation in the largest phase III randomized controlled trial completed in pNET patients. Methods: Patients with advanced low- or intermediate-grade pNET were randomly assigned to everolimus 10 mg/d orally + best supportive care (BSC; n = 207) or placebo + BSC (n = 203). Long-acting somatostatin analogs (SSAs) were permitted as BSC during the study. The primary endpoint was progression free survival (PFS). At progression (RECIST), patients could be unblinded and those randomly assigned to placebo were offered open-label everolimus. Results: Compared with placebo, everolimus reduced the risk of progression by 65% and increased median PFS by more than 6 months, from 4.6 to 11.0 months (HR = 0.35; 95% CI: 0.27-0.45; p < 0.0001), by investigator review (primary endpoint). Median PFS by central review was consistent (HR = 0.34; 95% CI: 0.26 to 0.44; p < 0.001] in favor of everolimus. Eighteen-month PFS estimates were 34% for everolimus (95% CI: 26-43) vs 9% (95% CI: 4-16) for placebo. Everolimus demonstrated a significant PFS benefit across all patient subgroups according to baseline characteristics and prior SSA use. Prior SSA use was 49% in the everolimus arm and 50% in the placebo arm. Updated analyses of the impact of concomitant SSA will be reported. The most common drug-related adverse events were stomatitis, rash, diarrhea, fatigue, and infections (primarily upper respiratory); most were grade 1 or 2. Stomatitis (6.9% vs 0%), anemia (6% vs 0%), and hyperglycemia (5% vs 2%) were the most common grade 3-4 events. Conclusions: Everolimus significantly prolonged PFS compared with placebo in patients with advanced pNET in this large phase III clinical trial. This benefit was seen across all patient subgroups. Treatment resulted in a significant 6.4-month prolongation in median PFS. Everolimus had an acceptable and predictable safety profile. [Table: see text]

Updated results from a phase III trial of sunitinib versus placebo in patients with progressive, unresectable, well-differentiated pancreatic neuroendocrine tumor (NET).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4118-4118 ◽  
Author(s):  
Aaron Vinik ◽  
Eric Van Cutsem ◽  
Patricia Niccoli ◽  
Jean-Luc Raoul ◽  
Yung-Jue Bang ◽  
...  
Keyword(s):  
Statistical Power ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Third Party ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Batch Mode ◽  
Phase Iii Trial ◽  
Well Differentiated

4118 Background: In a double-blind phase III trial, sunitinib (Sutent; SU) improved progression-free survival (PFS) vs placebo (PBO; 11.4 vs 5.5 mos; HR: 0.42, 95% CI: 0.26–0.66; P=0.0001) and was well tolerated in patients (pts) with unresectable, well-differentiated pancreatic NET that had progressed ≤12 mos before baseline. Initial overall survival (OS) revealed a benefit for SU vs PBO, although median OS had not been reached. We now report PFS assessed by blinded independent central review (BICR) and updated OS. Methods: Pts were randomized 1:1 to SU 37.5 mg or PBO on a continuous daily dosing schedule, each with best supportive care. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint to be evaluated every 2 yrs for 5 yrs, or until 95% of pts had died. Additionally, BICR was performed retrospectively; baseline and on-study CT/MRI scans were evaluated by a 2-reader, 2-time-point lock, followed by a sequential locked-read, batch-mode paradigm by blinded, third-party radiologists. Results: 171 pts were randomized (SU, n=86; PBO, n=85) from Jun 2007 to Apr 2009. The trial ended when an independent data monitoring committee noted efficacy favoring SU and more serious AEs and deaths with PBO. The study was unblinded at closure; pts were offered open-label SU and followed for survival. Median PFS by BICR was 12.6 mos (SU) vs 5.8 mos (PBO) (HR: 0.32, 95% CI: 0.18–0.55; P=0.00001). At study closure, there were 9 and 21 deaths in the SU and PBO arms (HR: 0.41, 95% CI: 0.19–0.89; P=0.02). By Apr 2011 (2 yrs additional follow-up) a total of 87 deaths occurred (51%), median OS was estimated at 33.0 mos in the SU arm, and 26.7 mos in the PBO arm (HR: 0.71, 95% CI: 0.47–1.09; P=0.11 [Table]). 69% of pts crossed over to SU on progression. Conclusions: BICR confirmed investigator assessment of PFS and demonstrated a 6.8-mo improvement in median PFS with SU. Updated OS favors SU, although this result is non-significant for reasons that may include crossover of treatment and limited statistical power. [Table: see text]

First-line use of cabazitaxel in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC): A three-arm study in comparison with docetaxel.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4696-TPS4696
Author(s):  
Stephane Oudard ◽  
Lisa Sengelov ◽  
Paul N. Mainwaring ◽  
Antoine Thiery- Vuillemin ◽  
Christine Theodore ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Current Standard ◽  
Open Label ◽  
Measurable Disease ◽  
Ecog Ps

TPS4696^ Background: Docetaxel (D) in combination with prednisone (P) as first-line (1L) chemotherapy in patients (pts) with mCRPC is the current standard of care. However, treatment is not curative and D-resistant disease typically develops. Cabazitaxel (Cbz) is a novel taxane active in D-sensitive and -resistant tumor models. Clinical activity of Cbz plus P (CbzP) was demonstrated in the Phase III TROPIC study in mCRPC pts previously treated with a D-containing regimen; CbzP showed a significant overall survival (OS) benefit vs mitoxantrone plus prednisone (median OS 15.1 vs 12.7 months; HR 0.70; P < 0.0001). Therefore, it is of interest to determine if CbzP provides an OS advantage vs DP in 1L mCRPC pts. Methods: The phase III FIRSTANA study (NCT01308567) is a randomized, open-label, multinational trial in 1L mCRPC pts, designed to compare the efficacy of Cbz 25 mg/m² IV Q3W (Arm A) and Cbz 20 mg/m² IV Q3W (Arm B) vs D 75 mg/m2 IV Q3W (Arm C). P 10 mg PO QD is to be given concomitantly. Pts are stratified by ECOG PS (0–1 vs 2), measurable disease (yes/no) and region (depending on availability of Cbz as 2L). Pts with ECOG PS ≤ 2, histologically/cytologically confirmed metastatic prostate adenocarcinoma, with no prior chemotherapy and with disease progression following medical or surgical castration are eligible. The primary endpoint is OS. Secondary endpoints include progression-free survival (PFS) (PCWG2 criteria), radiologic PFS, tumor response in measurable disease (RECIST 1.1), PSA response and PSA PFS, pain response and pain PFS, time to occurrence of any skeletal-related events, safety profile and health-related quality of life. Cbz pharmacokinetics and pharmacogenomics will be assessed in pt subgroups. Pts will be treated until progression, unacceptable toxicity or pt request. Planned enrollment is 1,170 pts; study size was calculated to achieve 90% power for OS. Study start was in May 2011; at January 2012, 219 pts were enrolled. The first DMC meeting recommended continuing the study without change.

Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): A multicenter, randomized, phase III study (PERSEUS).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS8055-TPS8055 ◽  
Author(s):  
Pieter Sonneveld ◽  
Annemiek Broijl ◽  
Francesca Gay ◽  
Mario Boccadoro ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
Stem Cell ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Open Label ◽  
Phase 3 ◽  
Related Quality ◽  
Duration Of Response ◽  
Line Of Therapy

TPS8055 Background: DARA, a human, CD38-targeting, IgGκ monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory MM (RRMM), and in combination with standard-of-care regimens in RRMM and transplant-ineligible NDMM. Given the initial safety and efficacy observed with DARA plus VRd (D-VRd) in the safety run-in cohort of the ongoing phase 2 GRIFFIN study in TE NDMM pts, the phase 3 PERSEUS study will evaluate the efficacy and safety of D-VRd versus VRd alone in TE NDMM. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd versus VRd alone in TE NDMM pts. Approximately 690 pts across Europe will be stratified by ISS stage and cytogenetic risk (high risk defined as presence of del17p, t[4;14], or t[14;16]) and randomized in a 1:1 ratio. All pts will receive VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-21; d: 40 mg PO Days 1-4, 9-12) for 4 pre-transplant induction and 2 post-transplant consolidation cycles (all 28-d cycles), followed by R (10 mg PO Days 1-28) maintenance until progressive disease (PD). Pts in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W in maintenance Cycles 7+ until PD. After induction, pts will undergo melphalan 200 mg/m2 conditioning and autologous stem cell transplantation (ASCT). Pts in the DARA group who achieve sustained minimal residual disease (MRD) negativity (10–5 threshold; assessed by NGS) for 12 months after ≥24 months of maintenance will stop DARA but continue R maintenance until PD; upon loss of CR or MRD-negative status, pts will restart DARA treatment. All pts will receive preinfusion medications. The primary endpoint is progression-free survival (PFS). Secondary endpoints include MRD-negative rate, overall response rate, PFS on next line of therapy, overall survival, time to and duration of response, health-related quality of life, pharmacokinetics, immunogenicity, stem cell yield after mobilization, time to engraftment post-ASCT, and safety. Clinical trial information: NCT03710603.

AcceleRET Lung: A phase III study of first-line pralsetinib in patients (pts) with RET-fusion+ advanced/metastatic non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9633-TPS9633 ◽  
Author(s):  
Benjamin Besse ◽  
Enriqueta Felip ◽  
Corinne Clifford ◽  
Melinda Louie-Gao ◽  
Jennifer Green ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Survival Duration ◽  
First Line ◽  
Open Label ◽  
Eligibility Criteria ◽  
Multiple Tumor ◽  
Platinum Based Chemotherapy

TPS9633 Background: RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1-2% of NSCLC, but no selective RET inhibitors are approved for use. The investigational RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multikinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), pts with RET-fusion+ NSCLC treated with 400 mg once daily (QD) of pralsetinib (N = 80) after platinum-based chemotherapy achieved an overall response rate (ORR) of 61% (95% CI 50, 72; 2 responses pending confirmation) per independent central review. In addition, a promising ORR of 73% (all centrally confirmed responses) was attained in the treatment naïve cohort (N = 26). Most treatment-related adverse events were grade 1-2 across the entire safety population treated at 400 mg QD (N = 354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) for first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). Methods: Approximately 250 pts with metastatic RET-fusion+ NSCLC will be randomized 1:1 to oral pralsetinib (400 mg QD) or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for metastatic disease; RET-fusion+ tumor by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; measurable disease per RECIST v1.1. Pts randomized to SOC will be permitted to cross-over to receive pralsetinib upon disease progression. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability and quality of life evaluations. Recruitment has begun with sites (active or planned) in North America, Europe and Asia. Clinical trial information: NCT04222972 .

A phase (Ph) 1b/2 study of ribociclib (R) in combination with docetaxel (D) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5043-5043
Author(s):  
Ivan de Kouchkovsky ◽  
Arpit Rao ◽  
Benedito A. Carneiro ◽  
Li Zhang ◽  
Catriona Lewis ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Single Agent ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Rank Test ◽  
Synergistic Activity ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Increased Risk

5043 Background: The survival benefit of D in mCRPC is modest. CDK4/6 inhibitors such as R have shown synergistic activity with taxanes in pre-clinical cancer models. We sought to determine the safety and efficacy of R + D + P in mCRPC patients (pts). Methods: This was a Ph 1b/2 multicenter, open-label single arm trial of mCRPC pts with progression (PD) on ≥ 1 prior androgen receptor signaling inhibitor (ARSi) who had not previously received D for mCRPC (NCT02494921). Pts were treated with escalating doses of R in combination with D + P for 6-9 cycles, followed by single agent maintenance R until radiographic or clinical PD. The Ph 2 primary endpoint was 6-month (mo) radiographic progression-free survival (rPFS) rate by PCWG2 criteria, with a target rate of 55% and null hypothesis of 35%. Ph 2 pts underwent baseline circulating tumor cell (CTC) enumeration and genome sequencing (Epic Sciences). Cox proportional hazard model and log-rank test were used to test for associations between rPFS and CTC burden and copy number (CN) variants, respectively. Results: 43 pts were enrolled from 11/2015 to 6/2019. Median age was 68 (range 55-84). 20.9% of pts had visceral metastases. 33 (77%) had PD on prior abiraterone, 27 (63%) on enzalutamide, and 17 (40%) on both. In Ph 1b, 19 pts were enrolled. In the first cohort (D 75 mg/m2 day [d] 1, R 200 mg/d d2-14 of every 21d cycle), 2 pts experienced DLTs (febrile neutropenia [FN] and grade 4 neutropenia). With an alternative dosing schema of D 60 mg/m2 on d1, and R daily on d1-4 and 8-15 of cycle, with daily G-CSF support on d5-7, the MTD was not reached and D 60 mg/m2 + R 400 mg/d was chosen as the recommended Ph 2 dose (RP2D). In total, 30 pts were treated at RP2D; median number of D cycles was 8.5 and 60% went on to receive maintenance R. The Ph 2 primary endpoint was met with a 6-mo rPFS rate of 65% (95% CI 50-85%). Median rPFS was 8.0 mos (95% CI 4.1-10.0). PSA response rate (RR) defined as ≥50% reduction was 27.6% (95% CI 12.7-47.2%) and objective RR was 30.8% (95% CI 9.1-61.4%). Among pts treated at RP2D, the most common grade ≥3 treatment-related adverse events were neutropenia (n= 11, 36.7%), lymphocytopenia (n=3, 10%); no cases of FN were observed. Baseline CTC burden was associated with an increased risk of radiographic PD or death (HR 1.038, 95% CI 1.001-1.074, p = 0.038). Pts harboring CTCs without MYC (4/11 pts) or CDK6 CN gain (7/11 pts) had prolonged rPFS compared to those with gene amplification (median rPFS 10.76 vs 4.11 mos, p = 0.03, and 7.01 vs 1.92 mos, p = 0.053, respectively). Conclusions: The combination of R + D was well tolerated and showed promising activity in mCRPC pts who had progressed on an ARSi. The Ph 2 study met its primary endpoint, with an encouraging 6-mo rPFS rate of 65%. Lack of MYC or CDK6 amplification on CTC sequencing was associated with longer rPFS. Funding: Novartis Pharmaceuticals, PCF YIA. Managed by the PCCTC. Clinical trial information: NCT02494921.

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