A phase I/II trial of melphalan (MEL) combined with panobinostat (PAN) for patients with relapsed or refractory (R/R) multiple myeloma (MM).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18558-e18558 ◽  
Author(s):  
Ori Yellin ◽  
James R. Berenson ◽  
Ralph V. Boccia ◽  
Allen Lee Cohn ◽  
Paul Berard ◽  
...  
Keyword(s):  
Phase 1 ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Treatment Schedule ◽  
Open Label ◽  
Dose Escalation Study ◽  
Heavily Pretreated ◽  
Label Dose ◽  
Dose Oral

e18558 Background: PAN, a potent histone deacetylase inhibitor, significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity of standard chemotherapy. Studies with our SCID-hu MM models show an increased inhibition of MM cell growth when PAN was combined with MEL compared to treatment with either drug alone. These preclinical studies provided the rationale for evaluating the combination of oral MEL with oral PAN for the treatment of MM patients with R/R disease. Methods: This was a Phase 1/2, open-label, dose‑escalation study to treat R/R MM patients initially using oral PAN every Monday, Wednesday and Fridayin combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28‑day cycle. Results: Thirty-seven patients were enrolled into the Phase 1 portion of this study. The median number of prior regimens received were 4 (range, 1-17) with 22 patients previously treated with MEL. Following amendments to dose and schedule because of toxicity including cytopenias and fatigue, PAN and MEL were both administered only on days 1, 3 and 5 of a 28-day cycle. The maximum tolerated dose for this combination was defined as PAN at 20 mg and MEL at 0.05 mg/kg both administered on only days 1, 3 and 5. Overall, 4 patients (11%) showed objective responses to this combination with 1 complete (3%) and 3 partial (8%) responses and only occurred among patients receiving PAN throughout the cycle. An additional 18 (49%) patients had stable disease while 15 (41%) progressed while on study. Eighteen patients experienced grade 3 or 4 adverse events (AEs) with 6 of these meeting the definition of a dose-limiting toxicity. These AEs included reversible thrombocytopenia (n=11), reversible neutropenia (n=10), reversible worsening anemia (n=3), and one case each of a forearm rash, fatigue/weakness, pneumonia, hypokalemia and hyponatremia. Three more patients who are not yet evaluable have been enrolled into the Phase 2 portion to complete the planned 40 patients on the trial. Conclusions: The combination of intermittent PAN & low-dose oral MEL shows modest activity in heavily pretreated patients with R/R MM. Continuous doses of PAN with MEL yielded better efficacy but this treatment schedule was not tolerable.

First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8500-8500 ◽  
Author(s):  
Paul G. Richardson ◽  
Annette J. Vangsted ◽  
Karthik Ramasamy ◽  
Suzanne Trudel ◽  
Joaquín Martínez ◽  
...  
Keyword(s):  
Plasma Cells ◽  
Phase 1 ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Dose Escalation Study ◽  
Tumoricidal Activity ◽  
Evaluable Population ◽  
Heavily Pretreated ◽  
Grade 3

8500 Background: CC-92480 is a novel cereblon E3 ligase modulator (CELMoD) agent designed for rapid, maximal degradation of Ikaros and Aiolos. In vitro, it has enhanced antiproliferative and tumoricidal activity in MM cell lines, including those resistant to lenalidomide (LEN) and pomalidomide (POM), with strong immune stimulatory activity. Methods: A phase 1, multicenter, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose, safety, tolerability, and pharmacokinetics of CC-92480 + DEX in heavily pretreated RRMM pts. Eligible pts had progression on or within 60 days of their last MM therapy and were either resistant or intolerant to, or not otherwise candidates for currently available therapies. Several treatment schedules tested escalating doses of CC-92480 + DEX (40 mg; 20 mg if ≥75 yrs). Results: As of Dec 24, 2019, 66 pts had received CC-92480 + DEX. Median age was 67 yrs (range 40–78), median number of prior regimens was 6 (range 2–13). Prior therapies included stem cell transplantation (67%), bortezomib (92%), LEN (89%), POM (83%), and anti-CD38 antibodies (78%). CC-92480 doses explored included 0.1–1.0 mg QD (10/14 days × 2), 0.8–1.0 mg QD (21/28 days), 0.2–0.8 mg BID (3/14 days × 2), and 1.6–2.0 mg QD (7/14 days × 2). MTD was 1.0 mg for both 10/14 × 2 and 21/28 schedules. Grade 3–4 treatment-emergent adverse events (TEAEs) were reported in 58 (88%) pts. Most frequent grade 3–4 TEAEs included neutropenia (53%), infections (30%), anemia (29%), and thrombocytopenia (17%), with 9% grade 3 fatigue. Among different cohorts,10 pts had dose-limiting toxicities (the majority related to neutropenia). Overall response rate (ORR) was 21% (9 very good partial responses [VGPRs]; 5 PRs) for efficacy evaluable population (n = 66). Efficacy was dose and schedule dependent; across two 1.0 mg QD schedules (10/14 × 2 and 21/28), 10 of 21 (48%) pts responded (7 VGPR and 3 PR), with response independent of immunomodulatory drug (IMiD) refractoriness. Plasma exposure increase and peripheral blood Ikaros and Aiolos degradation were dose dependent. Ikaros and Aiolos significantly decreased in bone marrow plasma cells of LEN- and POM-refractory pts. Conclusions: TEAEs of CC-92480 were mainly related to myelosuppression in heavily pretreated, including triple-class-refractory, RRMM pts. Promising activity with 48% ORR at therapeutic doses was observed. The study is ongoing to further optimize dose and schedule, with combination studies underway and dose expansion cohorts planned. Clinical trial information: NCT03374085 .

scholarly journals A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma

Blood ◽  
2012 ◽  
Vol 120 (3) ◽  
pp. 552-559 ◽  
Author(s):  
Jeffrey A. Zonder ◽  
Ann F. Mohrbacher ◽  
Seema Singhal ◽  
Frits van Rhee ◽  
William I. Bensinger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Stable Disease ◽  
Plasma Cells ◽  
Phase 1 ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Abstract This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow–derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

Phase I clinical study of cabazitaxel plus prednisolone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a Japanese population.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 237-237
Author(s):  
Shunji Takahashi ◽  
Hirofumi Mukai ◽  
Hirotsugu Uemura ◽  
Hiroji Uemura ◽  
Takeo Kosaka ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Label Dose ◽  
Expansion Cohort ◽  
Ecog Ps

237 Background: Cabazitaxel (CBZ), a novel taxoid agent, promotes tubulin assembly and stabilizes microtubules, as docetaxel (DTX). CBZ had antitumor activity in DTX-resistant tumor models in vitro. We assessed dose-limiting toxicities (DLTs), safety and efficacy of CBZ in patients (pts) with mCRPC with prior DTX treatment. Methods: This was an open-label, dose escalation study of CBZ every 3 weeks, with daily prednisolone. Two CBZ dose levels (20 or 25 mg/m2) were set in the dose escalation cohort to determine the maximum tolerated dose (MTD). Pts in the expansion cohort received the MTD. DLTs were evaluated at cycle 1 and were defined as follows: Grade (Gr) 4 neutropenia > 7 days, Gr 4 thrombocytopenia, Gr 4 febrile neutropenia (FN), or Gr 3/4 non-hematological toxicities. Gr 3/4 neutropenia was prospectively studied based on occurrence of Gr 3/4 neutropenia during prior DTX treatment. Results: A total of 48 pts received CBZ (median age 66.1 years; ECOG PS: 0, 34 pts; 1, 14 pts; median cumulative DTX dose 753 mg/m2). None of the evaluable pts in the dose escalation cohort experienced a DLT. All pts had at least one Gr 3/4 adverse event (AE). Frequent Gr 3/4 AEs at 25 mg/m2 were neutropenia (44 pts, 100%) and FN (24 pts, 54.5%). G-CSF prophylaxis was not allowed at cycle 1 and was only used in 10% of cycles from cycle 2 onward. Neutropenia occurrence during prior DTX treatment did not affect neutropenia or FN incidence during CBZ treatment. No pt discontinued CBZ due to neutropenia or FN and no toxic death was reported. In total, 12/41 pts (29.3%) had a PSA response, and 2/12 evaluable pts had a partial response as the best overall response. Conclusions: The safety profile of CBZ in Japanese pts was generally consistent with that reported in previous studies. The cumulative dose of prior DTX was higher and use of G-CSF prophylaxis less frequent than in previous studies, which may have contributed to the increased incidence of neutropenia and FN in Japanese pts. The majority of neutropenia and FN events were manageable and did not lead to treatment discontinuation. In terms of safety and efficacy, CBZ has a favourable risk–benefit profile in Japanese pts with mCRPC following prior DTX therapy. Clinical trial information: NCT01324583.

scholarly journals Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma

2021 ◽  
Vol 11 (2) ◽  
Author(s):  
Jacob P. Laubach ◽  
Sascha A. Tuchman ◽  
Jacalyn M. Rosenblatt ◽  
Constantine S. Mitsiades ◽  
Kathleen Colson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Duration Of Response ◽  
Label Dose ◽  
Grade 3

AbstractAdditional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

scholarly journals A phase 1/2, open‐label, dose‐escalation study of midostaurin in children with relapsed or refractory acute leukaemia

2018 ◽  
Vol 185 (3) ◽  
pp. 623-627 ◽  
Author(s):  
C. Michel Zwaan ◽  
Stefan Söderhäll ◽  
Benoit Brethon ◽  
Matteo Luciani ◽  
Carmelo Rizzari ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Acute Leukaemia ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Phase 1, open-label, dose-escalation study of sorafenib in combination with eribulin in patients with advanced, metastatic, or refractory solid tumors

2018 ◽  
Vol 81 (4) ◽  
pp. 727-737 ◽  
Author(s):  
Frederik Marmé ◽  
Carlos Gomez-Roca ◽  
Kristina Graudenz ◽  
Funan Huang ◽  
John Lettieri ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose

Phase I open-label, dose escalation of YH003, an anti-CD40 monoclonal antibody in combination with toripalimab (anti-PD-1 mAb) in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2580-2580
Author(s):  
Jermaine Coward ◽  
Afaf Abed ◽  
Adnan Nagrial ◽  
Ben Markman
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Dose Escalation Study ◽  
Label Dose ◽  
Febrile Episodes ◽  
Antigen Presenting

2580 Background: YH003, a recombinant, humanized agonistic anti-CD40 IgG2 monoclonal antibody (mAb) specifically recognizes and agonizes CD40 on the antigen-presenting cells to enhance immune responses. Preclinical data have shown potent anti-cancer activity when combined with anti-PD-1 antibodies. Methods: This is an ongoing phase 1 dose-escalation study. Patients with advanced solid tumors receive YH003 by IV administration Q3W as monotherapy at 0.03 to 3.0 mg/kg for the first cycle (21 days) then in combination with Toripalimab at 240 mg Q3W for the 4 subsequent cycles in an accelerated “3+3” design. The safety, tolerability and preliminary efficacy data will be analyzed. Results: As of 31 Dec 2020 data cutoff, 9 patients (pts) were enrolled and treated at 0.03 mg/kg (n = 3), 0.1mg/kg (n = 3), and 0.3mg/kg (n = 3). The median age was 63 years (range 33-68). Baseline ECOG scores were 0 (7 pts) and 1 (2 pts) with a median of 2 prior lines therapy (range 1-7). 5 pts had received prior immunotherapy (PD-1/PD-L1 or PD-1+CTLA-4). As of data cutoff, no dose limiting toxicities (DLT) were observed. No Serious Adverse Event (SAE) or AEs leading to treatment discontinuation were reported. Four drug related AEs were reported including one Grade 1 (G1) choroidal thickening (related to YH003) at 0.03 mg/kg, one G1 fatigue (related to YH003) at 0.1 mg/kg, two G1 febrile episodes (one related to YH003 and the other related to combination treatment) at 0.3 mg/kg. Among 5 patients assessable for response, there were 2 SD (one with anti-PDL1 refractory Merkel cell carcinoma at 0.03 mg/kg and one with anti-PD1 refractory NSCLC at 0.1 mg/kg) and 1 PR with anti-PD1/anti-CTLA4 refractory ocular melanoma at 0.1 mg/kg. Conclusions: YH003 was well tolerated up to 0.3 mg/kg dose levels when combined with Toripalimab and has shown encouraging antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04481009.

A Phase I/II National, Multi-Center, Open-Label Study of Bortezomib Plus Melphalan and Prednisone (V-MP) in Elderly Untreated Multiple Myeloma (MM) Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 786-786 ◽  
Author(s):  
M.V. Mateos ◽  
M. Hernández ◽  
J. Díaz Mediavilla ◽  
L. Palomera ◽  
M.J. Moro ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Response Rate ◽  
Haematological Toxicity ◽  
Maximum Tolerated Dose ◽  
Cytotoxic Agents ◽  
Treatment Schedule ◽  
Significant Activity ◽  
Open Label ◽  
Minor Response

Abstract Background: Although clearly unsatisfactory, melphalan and prednisone remains the gold standard for elderly MM patients. Therefore new treatment strategies are needed for these patients. The proteasome inhibitor bortezomib (VELCADE) has shown significant activity in refractory/relapsed MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan. Aim: To define the appropriate dose of bortezomib in combination with MP and to analyse the toxicity and efficacy of V-MP (in terms of response) in untreated MM pts ≥ 65 years old. Methods: Treatment schedule consisting of four 6-week cycles followed by five 5-week cycles. First, two sequential dose levels of bortezomib (1.0 and 1.3 mg/m2) (6 pts each) were explored, administered on days 1,4,8,11,22,25,29 and 32 in combination with oral melphalan, 9 mg/m2 and prednisone, 60mg/m2 once daily on days 1 to 4. When maximum tolerated dose (MTD) of bortezomib in combination with MP was defined, the cohort of pts at the MTD was expanded to up to 60 patients to further refine estimates of efficacy and toxicity (PhaseII). Results: Median age of the 60 enrolled pts was 74(65–85) and the median number of cycles so far received is 3(1–9). During PhaseI, no dose limiting toxicity(DLT) was observed in the two cohorts of pts, and the recommended dose for phaseII was 1.3 mg/m2 of bortezomib in combination with MP. 53pts are evaluable for efficacy since they have already completed at least the first cycle. Analysis of response after cycle 1 revealed a Response Rate(RR) of 72%(6%CR with Immunofixation negative(CRIF-), 2%CRIF+ and 64%Partial Response(PR)). Analysis of best response after a median of 3 cycles revealed a RR of 85%(28%CRIF-, 11%CRIF+ and 45%PR); an additional pt(2%) achieved Minor Response(MR) and 7(13%) stable disease. The toxicity was manageable. Adverse events G3-4 reported for 60 pts included: Gastrointestinal toxicity, such as nauseas(2%), vomiting(2%), diarrhoea(15%) and constipation(8%); haematological toxicity, such as anemia(12%), neutropenia(G3 in 26% and G4 in 13%) and thrombocytopenia(G3 in 33% and G4 in 13%); infection(G3 en 12% and G4 in 2%) and peripheral neuropathy(G3 in 13% and G4 in 2%). Bortezomib and melphalan dose modification was required in 6 and 2 pts, respectively. Eight pts so far have been discontinued due to toxicity related to study medication: peripheral neuropathy in 5(G2 in 1, G3 in 2 and G4 in 2), diarrhoea in 1(G3), infection in 1(G3) and prolonged thrombocytopenia in 1(G4). With a median follow up of 7 months (range:3–15), two responding pts have progressed (months +9and+10), 54(90%) are alive and 6(10%) have died. Cause of death was lung cancer diagnosed 1 month after start of study treatment(1), progressive disease(1), septic shock(2), pulmonary thromboembolism (1) and pulmonary hypertension with right ventricular insufficiency and multiorganic failure(1). Conclusion: V-MP shows a high response rate(85% with 28%CRIF-) and manageable toxicities and could replace MP as the standard of care for elderly MM pts. An international phase 3 randomized trial is in progress to examine this.

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