Updates in Clinical Data on FDA Fast Track Drugs for Relapsed Refractory Multiple Myeloma: A Systematic Review of Literature

Introduction FDA (Food and Drug Administration) fast track program facilitates the development and accelerated review of new drugs aimed at treating life-threatening conditions and having the potential to address unmet medical needs. FDA fast track drugs (2019) for relapsed refractory MM include selective exportin-1 (XPO-1) inhibitors, first generation Selinexor / KPT-330 (S) and second generation KPT-8602, and an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE), AMG-420. The aim of our study is to analyze published literature for updates in clinical data viz efficacy and toxicity of these new agents in pts with RRMM. Methods Following PRISMA guidelines, we performed a comprehensive literature search on articles published after 2014 using Pubmed, Embase, Cochrane and Web of Science. Fifty-eight articles were identified initially and after a detailed scrutiny, we finalized 8 studies involving 299 RRMM patients and summarized the data using absolute values and percentages. Chimeric antigen receptor (CAR) T-cell therapy was excluded from our manuscript. Results Selinexor / KPT-330: A total of 6 studies (Table 1) involving 258 RRMM pts were included. In a phase Ib/II study by Bahlis et al., S was given in combination with bortezomib (V) and dexamethasone (d) to 22 pts with 4 median prior lines of therapy. The overall response rate (ORR) was 77% with complete response (CR) in 5%, partial response (PR) in 50% and very good partial response (VGPR) in 23% pts. In another phase Ib/II study by the same author, SVd was given to 42 pts with 3 median prior therapies. In 40 evaluable pts, ORR was 63% with CR in 8%, PR in 33%, and VGPR in 23%. The progression free survival (PFS) was 9 months. In a phase I/II study by Broijl et al., S (45 or 30 mg/m2) was given in combination with Vd to pts with median 3 prior treatments. Among 5 evaluable pts who received 45 mg/m2 of S, PR was observed in 80% and VGPR was observed in 40% pts. OS was 100% and 75% at 12 and 24 months respectively and PFS was 17 months. In pts who received S (30 mg/m2) with Vd, PR was observed in 67% and VGPR was observed in 17% pts. OS was 75% at 12 months and PFS was 10 months. In a phase II study by Vogl et al, 79 pts received S (80 mg) in combination with d (20 mg), both orally and twice weekly. Median prior therapies received were 7. In 78 evaluable patients, the ORR was 21% with PR in 15% and VGPR in 5%. OS and PFS were 9.3 and 2.3 months respectively. In a phase I study by Chen et al., 84 pts having received 6 median prior therapies were included. S was given either alone or in combination with d. Fourteen pts were rendered ineligible for response. ORR was 4% for pts who received single-agent S and 22% for those who received S+d. PR was observed in 4% of single-agent S pts. Among S+d pts, all responses were observed in S (45 mg/m2) plus d (20 mg) group (ORR 50%) with CR in 8% and PR in 42% pts. In a phase I study by Jakobowiak et al., 18 pts with median 3 prior therapies were included. S in combination with carfilzomib (CFZ) and d were given. Among 16 evaluable patients, PR was observed in 63% and VGPR was observed in 25% pts. On July 3, 2019, FDA granted accelerated approval to selinexor. KP-8602: In a phase I/II trial by Cornell et al., involving 6 pts, KP-8602 (5 mg PO QDx5) in combination with dexamethasone (20 mg 2QWK) was given for 28 days. they had received 6 median prior lines of therapy. PR was observed in 16% of the pts. AMG-420: In a phase I study by Topp et al., 35 pts with median 4 prior lines of therapy were included. Single-agent AMG-420 (0.2-800 µg/day) was given. CR was observed in 17% pts. The highest dose at which a CR was observed was 400 µg/day. It was also the dose at which maximum number of pts showed a CR (n=3, 9%). A partial response (PR) and a very good partial response (VGPR) was also observed in 1 patient each i.e. 3%. Conclusion Combination regimens of SVd has superior efficacy as compared to S monotherapy. Major adverse events reported with both single-agent and combination regimens are hematological i.e. thrombocytopenia, neutropenia and anemia. KP-8602 has promising efficacy in limited pts and appear to have better adverse effect profile. AMG-420 has shown promising activity and tolerability in RRMM pts at a dose of 400 µg/day with no major toxicities at this dose. The published data on these drugs is scarce, still emerging and warrants further investigation. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

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A phase I study of the safety and pharmacodynamic effects of everolimus in combination with lenalidomide in patients with advanced solid malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2576 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2576-2576 ◽

Cited By ~ 1

Author(s):

Taofeek Kunle Owonikoko ◽

R Donald Harvey ◽

John S Kauh ◽

Colleen Margaret Lewis ◽

Mohammed S Hossain ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Phase I Study ◽

Mtor Inhibitor ◽

Single Agent ◽

Cell Subset ◽

T Cell Subsets ◽

Cytotoxic T Cell ◽

Multiparameter Flow Cytometry ◽

Solid Malignancies

2576 Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are both potent anti cancer agents with immunomodulatory effects. Preclinical evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor and lenalidomide provided the rationale for this phase I study. Methods: Patients with advanced solid malignancies, ECOG performance status (PS) 0-2 and adequate organ function were eligible. Using standard 3+3 dose escalation schema, patients were treated in cohorts of three with increasing doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day cycle. Treatment cycles were repeated until disease progression by RECIST criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment on circulating B and T lymphocytes subsets were assessed by multiparameter flow cytometry at baseline and after 2 cycles. Results: We enrolled 21 patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5); median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%) without dose limiting toxicities. The median number of completed cycles was 3 (1 - ≥15) and best response in 14 of 18 evaluable patients was stable disease (range 2- ≥14 months); median PFS was 116 days (14- ≥498). The RP2D of E and L was defined as 10mg and 25mg once daily, respectively. PD endpoint analysis after 2 cycles of treatment showed a significant increase in activated cytotoxic T cell subset (CD8+ICOS1+) in patients with salivary or thyroid cancers compared to other tumor types (+2051.0 vs. +394 vs. -1687.4 respectively; p=0.0303) and a trend for an increase in patients with non-progressing tumors (+661.7 vs. -384.1; p=0.0988). Other significant correlations were: Changes in total B-cells (CD3-CD19+) with PFS; NK cells with age (p=0.0211) and activated T cells (CD3+CD69+; CD3+CD62L-; p=0.01) with gender. Conclusions: The combination of E and L is well tolerated at the recommended single agent doses and showed promising efficacy in neuroendocrine and salivary adenoidcystic carcinoma. Modulation of activated T cell subsets (CD8+ICOS1+) correlates with efficacy of these agents.

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Phase I Study of Lorvotuzumab Mertansine (IMGN901) In Combination with Lenalidomide and Dexamethasone In Patients with CD56-Positive Relapsed or Relapsed/Refractory Mulitple Myeloma - A Preliminary Safety and Efficacy Analysis of the Combination

Blood ◽

10.1182/blood.v116.21.1934.1934 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1934-1934 ◽

Cited By ~ 5

Author(s):

Jesus G Berdeja ◽

Sikander Ailawadhi ◽

Ruben Niesvizky ◽

Jeffrey L Wolf ◽

Sybil H Zildjian ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Dose Level ◽

Phase I Study ◽

Single Agent ◽

The Other ◽

Clinical Activity ◽

Serious Adverse Events ◽

Dose Cohort ◽

Objective Evidence

Abstract Abstract 1934 Background: Lorvotuzumab mertansine, also known as IMGN901 (huN901-DM1/BB-10901) is a novel anticancer agent consisting of a potent cytotoxic maytansinoid, DM1, attached to a CD56-binding monoclonal antibody, lorvotuzumab, using an engineered disulfide linker. Once bound to CD56 on a cancer cell and internalized, the conjugate releases DM1. About 78% of multiple myeloma (MM) cases have strong surface expression of CD56. In preclinical settings, IMGN901 showed significant in vitro and in vivo anti-myeloma activity as a single agent and in combination with approved drugs such as lenalidomide. IMGN901 has also been shown to be active and well tolerated as a single agent in a separate phase I study in patients with relapsed or relapsed/refractory MM. Objectives: To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetics (PK), and activity of IMGN901 in combination with lenalidomide and dexamethasone in patients with MM. Methods: Patients with CD56+ relapsed or relapsed/refractory MM receive IMGN901once weekly for 3 consecutive weeks every 4 weeks (Days 1, 8, 15 every 28 days). Lenalidomide (25mg) is taken orally once daily on Days 1 to 21 every 28 days and dexamethasone (40mg) is taken orally once weekly for 4 weeks (Days 1, 8, 15, and 22 every 28 days). The doses of lenalidomide and dexamethasone will remain fixed while escalating dose levels of IMGN901 are assessed. Patients are enrolled into each dose level in cohorts of 3, with DLTs triggering cohort expansion. Pharmacokinetics of IMGN901 and lenalidomide at the MTD will be collected, with exploratory pharmacodynamic studies planned. Results: The first dose cohort (75mg/m2 IMGN901) has been fully enrolled and accrual to the second dose cohort (90mg/m2) has commenced. There has been no DLT, no serious adverse events, and no drug-related grade 3 or 4 toxicities. Among the three patients enrolled in the 75mg/m2 dose cohort, by the end of cycle 2, one withdrew secondary to progressive disease (PD) and the other two had achieved a partial response (PR) based on the International Uniform Response Criteria for MM; the two patients with PRs remain on study. One of these patients had received 3 prior lines of therapy plus a transplant. This patient's PR has since improved to a very good partial response (as of end of Cycle 3). The other responding patient had received 4 prior treatment regimens plus 2 transplants. Conclusions: In this assessment of IMGN901 used in combination with lenalidomide and dexamethasone in patients with CD56+ relapsed or relapsed/refractory MM, objective evidence of clinical activity has been observed in two of the three patients who received the first dose level of IMGN901 evaluated. The combination has been well tolerated to date, MTD has not been defined and dose escalation continues. This very early experience is encouraging and supports the continued assessment of IMGN901 used in combination with lenalidomide and dexamethasone for patients with CD56+ relapsed or relapsed/refractory MM. Disclosures: Ailawadhi: Celgene: Speakers Bureau. Zildjian:ImmunoGen, Inc.: Employment. O'Leary:ImmunoGen, Inc.: Employment.

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EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.141 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii307-iii307

Author(s):

Mariko DeWire ◽

James Leach ◽

Christine Fuller ◽

Peter de Blank ◽

Trent Hummel ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Single Agent ◽

Maximum Tolerated Dose ◽

Pharmacokinetic Studies ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas ◽

Grade 3 ◽

Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

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EPCT-17. A PHASE I AND SURGICAL STUDY OF RIBOCICLIB AND EVEROLIMUS IN CHILDREN WITH RECURRENT OR REFRACTORY MALIGNANT BRAIN TUMORS: PEDIATRIC BRAIN TUMOR CONSORTIUM INTERIM REPORT

Neuro-Oncology ◽

10.1093/neuonc/noaa222.139 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii307-iii307

Author(s):

Mariko DeWire ◽

Christine Fuller ◽

Olivia Campagne ◽

Tong Lin ◽

Haitao Pan ◽

...

Keyword(s):

Brain Tumors ◽

Phase I ◽

Dose Level ◽

Phase I Study ◽

Single Agent ◽

Pediatric Brain Tumor ◽

Pi3k Pathway ◽

Neurosurgical Procedures ◽

Common Grade ◽

Grade 3

Abstract Genomic aberrations in the cell cycle and PI3K pathway are commonly observed in recurrent childhood brain tumors. Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dosage (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus was determined in the Phase I study and ribociclib concentrations were characterized in plasma and tumor in children undergoing neurosurgical procedures. Following resection, eligible patients were enrolled in the Phase I study according to a rolling 6 design and received ribociclib and everolimus once daily for 21 days and 28 days, respectively. Patients undergoing surgery received ribociclib at the pediatric RP2D (350 mg/m2/day) for 7–10 days pre-operatively. Pharmacokinetic samples were collected on both cohorts and analyzed in nine patients on phase I study. Sixteen eligible patients enrolled on phase I study (median age 10.3 years; range: 3.9–20.4) and 5 patients were enrolled on the surgical cohort (median age 11.4 years; range: 7.2–17.1). Six patients enrolled at dose level 1 without dose limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. Everolimus concentrations following administration of everolimus alone were lower than those following drug combination, suggesting an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus in recurrent CNS tumors is 120 mg/m2 and 1.2 mg/ m2 daily for 21 days and 28 days, respectively.

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Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

Journal of Clinical Oncology ◽

10.1200/jco.2013.52.3522 ◽

2015 ◽

Vol 33 (7) ◽

pp. 732-739 ◽

Cited By ~ 58

Author(s):

Kyriakos P. Papadopoulos ◽

David S. Siegel ◽

David H. Vesole ◽

Peter Lee ◽

Steven T. Rosen ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Concentration ◽

Phase I ◽

Phase I Study ◽

Low Dose ◽

Single Agent ◽

Phase Iii ◽

Maximum Plasma ◽

Irreversible Inhibitor ◽

Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

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A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3101 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3101-3101

Author(s):

Ying Cheng ◽

Ying Liu ◽

Jinhua Xu ◽

Jing Zhu ◽

Ying Wang ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Solid Tumors ◽

Renal Cancer ◽

Phase I Study ◽

Angiogenesis Inhibitor ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

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