Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic ...leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism–associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell–mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre–germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.
•Ibrutinib provided effective salvage therapy in CLL relapse post–alloHCT, resulting in sustained MRD negativity without GVHD development.•Ibrutinib selectively depleted pre–germinal B cells and Th2 helper cells and may enhance donor Th1 T-cell–mediated GVL effects.
Background To evaluate the safety of several doses of a new thrombolytic, TNK tissue-plasminogen activator (tPA), given as a single bolus to patients with acute myocardial infarction. Methods and ...Results A total of 3235 patients were given TNK-tPA: 1705 received 30 mg, 1457 received 40 mg, and 73 received 50 mg. The 50-mg dose was discontinued and replaced by 40 mg because of increased bleeding observed in the Thrombolysis In Myocardial Infarction (TIMI)-10B study, the phase II angiographic efficacy trial conducted in parallel with this study. The total stroke rate at 30 days in the trial was 1.5%. An intracranial hemorrhage was observed in 25 patients (0.77%): 16 in the 30-mg group (0.94%) and 9 in the 40-mg group (0.62%). No strokes occurred in the 73 patients treated with 50 mg TNK-tPA. In patients treated within 6 hours after symptom onset the rates of intracranial hemorrhage were 0.56% (30 mg TNK-tPA) and 0.58 (40 mg TNK-tPA). Death, death or nonfatal stroke, or severe bleeding complications occurred in a low proportion of patients: 6.4%, 7.4%, and 2.8%, respectively, without significant differences among the treatment groups. Conclusions The overall safety profile of a single bolus of 30 to 50 mg TNK-tPA is comparable to that of accelerated r-tPA observed in other large trials. The safety data from this trial and the patency data of TIMI-10B were the basis for a decision to conduct a large phase III mortality trial comparing weight-adjusted single-bolus TNK-tPA with accelerated r-tPA (ASSENT-2). (Am Heart J 1999;137:786-91.)
Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and ...perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI.
In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs.
Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome.
Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.
Summary
Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first‐in‐class, once‐daily, oral ...covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low‐dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2‐stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression‐free survival was 4·6 months (range, 0·4–17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non‐haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre‐treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.
Introduction
Ibrutinib is a first-in-class oral inhibitor of Bruton's tyrosine kinase approved for relapsed/refractory mantle cell lymphoma (R/R MCL). We previously reported results of a pooled ...analysis of 370 patients with R/R MCL treated with ibrutinib in the SPARK (MCL2001; NCT01599949), RAY (MCL3001; NCT01646021), and PCYC-1104 (NCT01236391) studies (median follow-up 24 months; Rule S et al, Br J Haematol in press). Here, we present median 3.5 year follow-up in these patients, including additional exposure and follow-up of 87 patients across the 3 studies who enrolled in the long-term access study CAN3001 (NCT01804686).
Methods
Patients enrolled in SPARK, RAY, and PCYC-1104 received ibrutinib 560 mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar except patients in SPARK were required to have received both rituximab and bortezomib, and in RAY, prior rituximab. Patients who continued to benefit from ibrutinib therapy at end of study were eligible to enroll in CAN3001, a phase 3b open-label study providing continued access to ibrutinib. Safety reporting in CAN3001 was limited to grade 3/4 adverse events (AEs) and serious adverse events (SAEs). This pooled analysis was limited to patients on ibrutinib therapy, excluding crossover patients. Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. PFS and OS were analyzed by number of prior lines of therapy (LOT) and best tumor response. Patients in CAN3001 were censored from OS analysis upon treatment or study discontinuation. Treatment-emergent adverse events (TEAEs) of ≥ grade 3 were summarized.
Results
Of a total 370 patients, 111 were enrolled in PCYC-1104, 120 in SPARK, and 139 in RAY; 87 of 370 patients subsequently enrolled in CAN3001. The median duration of follow-up in the pooled data set was 41.1 months (95% confidence interval CI, 37.3-42.5); median treatment exposure was 11.1 months (range: 0.03-72.1). Eighty-three and 40 patients had ibrutinib exposure ≥ 3 and ≥ 4 years, respectively. Fifty-four of 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib. Patients had a median of 2 (range: 1-9) prior LOT before receiving ibrutinib.
The proportion of patients achieving complete response (CR) increased to 26.5% with 41 months of follow-up. At 2 and 3 years, respectively, 36% (95% CI, 0.31-0.42) and 26% (0.20-0.32) of patients were progression free, and the median PFS was 13.0 months (Table). Median PFS in patients with 1 prior LOT was 33.6 (19.4-42.1) months (Figure) and in patients achieving CR was 46.2 (42.1-not estimable) months (Table). Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib > 3 years.
Overall, 53% (95% CI, 0.47-0.58), 45% (0.39-0.50), and 37% (0.25-0.49) of patients were alive at 2, 3, and 5 years, respectively. Median OS was 26.7 months (Table).
Grade ≥ 3 TEAEs occurred in 295 (79.7%) patients, with the new onset events decreasing after Year 1 (67.8%, 47.8%, 34.8%, 36.1%, and 20.0% for Years 1, 2, 3, 4, and > 4, respectively). Cumulative incidence of any major hemorrhage was 7.3%, and new onset events decreased after Year 1 (4.9%, 2.2%, 2.6%, 2.4%, and 0% for Years 1, 2, 3, 4, and > 4, respectively). The most common (incidence ≥ 5%) grade ≥ 3 TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%), and hypertension (5.1%). Most of these AEs were more common during the first year of ibrutinib treatment. Treatment-emergent SAEs occurred in 229 (61.9%) patients and new onset SAEs decreased over time (incidence: 47.3%, 33.9%, 29.6%, 25.3%, and 12.5% for Years 1, 2, 3, 4, and > 4, respectively).
Conclusion
In this pooled analysis of ibrutinib-treated R/R MCL patients with median 3.5 years of follow-up, more than a quarter of patients remained progression free and nearly half were alive at 3 years. Clinical outcomes were best for patients who achieved CR and those who were treated with ibrutinib at first relapse/progression. New onset grade ≥ 3 AEs/SAEs decreased over time.
Funding Source
This project was sponsored by Janssen. Writing assistance was provided by Natalie Dennis of PAREXEL and was funded by Janssen Global Services, LLC.
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Rule:Sunesis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Napp: Consultancy. Dreyling:Bayer: Consultancy, Speakers Bureau; Sandoz: Consultancy; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Mundipharma: Consultancy, Research Funding; MorphoSys AG: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau. Goy:Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hess:Celgene: Other: Grants and personal fees; Pfizer: Other: Grants and personal fees; Janssen: Other: Personal Fees; CTI: Other: Grants; Roche: Other: Grants and personal fees. Auer:Janssen: Other: Personal fees; Non-financial support; Bristol Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees. Kahl:Gilead: Other: Personal fees; Infinity: Other: Personal fees; Pharmacyclics: Other: Grants; Personal fees. Londhe:Janssen: Employment, Equity Ownership. Clow:Pharmacyclics: Employment. Deshpande:Janssen: Employment. Parisi:Janssen: Other: Janssen employee. Wang:Karyopharm: Research Funding; Oncoceutics: Research Funding; Juno Therapeutic: Research Funding; Asana: Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karus: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite Pharma: Research Funding; Oncternal: Research Funding; BeiGene: Research Funding; Novartis: Research Funding.
Introduction: As outcomes in patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) remain suboptimal, new, effective treatment options with a favorable safety profile are needed. ...Ibrutinib is a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase (BTK), a key component of B-cell signaling involved in B-cell survival, proliferation and function. In lymphomas, ibrutinib is FDA-approved for treatment of mantle cell lymphoma in pts with ≥1 prior therapy. A phase 1 dose-escalation study with ibrutinib showed single-agent activity in pts with R/R B-cell malignancies (overall response rate ORR 60%; complete remission CR in 16%) including FL (Advani JCO 2013). In this trial, the 560 mg/day fixed dose was well tolerated and led to full BTK occupancy. We evaluated the efficacy, safety, and tolerability of single-agent ibrutinib by low- vs. high-dose groups with longer follow-up in pts with relapsed FL.
Methods: Data were analyzed for pts with R/R FL (N=16) treated with oral ibrutinib in the phase I study (PCYC-04753), where pts received escalating doses of ibrutinib 1.25-12.5 mg/kg/day per cycle (1 cycle = 28 days + 7 days rest) or continuous doses of ibrutinib 8.3 mg/kg/day or 560 mg/day fixed dose (1 cycle = 35 days). Pts with stable disease or better, who received therapy for 6 months, continued ibrutinib at a fixed dose of 560 mg/day in the extension study (PCYC-1103) until progression or unacceptable toxicity. Pt data categories included low-dose (1.25 mg/kg/day, 2.5 mg/kg/day, or 5 mg/kg/day) or high-dose (8.3 mg/kg/day or 12.5 mg/kg/day) groups.
Results: Eight pts each were categorized into low-dose and high-dose groups. Baseline characteristics were similar, but median treatment duration was longer for the high-dose group (Table; 12 vs. 4 months). Increased ORR (63% vs. 25%) and CR rates (38% vs. 0%) were observed in the high-dose compared with low-dose group (Table). Median duration of response (DOR) was longer in the high-dose group (12 vs. 3 months), as was median progression-free survival (PFS; 24 vs. 9 months). Median overall survival (OS) was not reached (NR) in either group. Grade ≥3 adverse events (AEs) occurred in 3 pts in each group. Common grade ≥3 AEs reported in ≥3 pts in the combined groups included (low-dose, high-dose) diarrhea (n=2, 6), fatigue (n=3, 4), nausea (n=2, 4), cough (n=3, 2), myalgia (n=1, 3), headache (n=0, 3), muscle spasms (n=1, 2), pruritus (n=0, 3), and rash (n=0, 3). Serious AEs occurred in 3 pts in the low-dose and 1 pt in the high-dose group. AEs leading to treatment discontinuation occurred in 2 pts in each group. No fatal AEs occurred. Among 4 pts (high-dose group) receiving ibrutinib beyond 1 year (range, 18 to 61 months), no unexpected or increased AEs were observed; 1 pt experienced 2 grade 3 AEs (non-cardiac chest pain and vomiting), both within 60 days from start of treatment and lasting 1 day. No other grade ≥3 AEs occurred among these 4 pts.
Conclusions: Higher doses of single-agent ibrutinib were associated with increased response rates and prolonged PFS in pts with R/R FL. A higher dose was not associated with increased AEs or with cumulative toxicity during extended therapy. In the current analysis, pts with FL derived the most benefit from ibrutinib doses at 8.3 mg/kg/day or higher. A study testing single-agent ibrutinib at 560 mg/day in pts with R/R FL is ongoing (Bartlett Blood 2014) as is a phase 2 study evaluating ibrutinib 560 mg/day in chemoimmunotherapy refractory FL.
Table 1Patient Characteristics and EfficacyLow dose(n=8)High dose(n=8)Median age, yrs (range) Age ≥ 70 yrs, n (%)57 (48-70)1 (13)62.5 (41-71)1 (13)Median no. of prior therapies (range)3 (1-4)2 (1-5)Ann Arbor stage III/IV disease, n (%)6 (75)6 (75)FLIPI score, % (low / intermediate / high)*25 / 38 / 3813 / 38 / 50Median treatment duration, months (range)3.8 (0.5-11.1)12.4 (0.2-61.5)ORR, n (%) CR, n (%)2 (25)0 (0)5 (63)3 (38)Median DOR, months (range)n=2; 3.4 (1.8-4.9)n=5; 12.3 (4.8-51.3)Median PFS, months (95% CI)9.2 (0.5, 13.4)23.7 (2.2, NE)10-month PFS, %35.770Median OS, months (95% CI)NRNR10-month OS, %100100*FLIPI scores from baseline data. NE, not estimable
Off Label Use: single-agent ibrutinib therapy in patients with relapsed FL. Boyd:Celgene: Research Funding, Speakers Bureau; Genentech: Research Funding; US Oncology: Research Funding; GSK: Research Funding. Sharman:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Inc.: Research Funding; Janssen: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment.
Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without ...chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr and chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As the addition of obinutuzumab (G) to clb provides superior efficacy over clb alone or rituximab-G, we investigated the potential for improved efficacy with addition of G to single-agent ibr vs clb-G in an international, open-label, randomized phase 3 study (PCYC-1130; iLLUMINATE) in first-line CLL/SLL.
Methods: Eligible pts had previously untreated CLL/SLL requiring treatment per iwCLL criteria and were ≥65 years of age or were <65 years old with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation). Pts were randomized 1:1 to receive ibr (420 mg once daily continuously) combined with G (1000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles, for a total of 6 cycles), or clb (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles) combined with G (as above). Primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Secondary endpoints included PFS in high-risk population (del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV), rate of undetectable minimal residual disease (MRD), overall response rate (ORR), overall survival (OS), and safety. Pts with IRC-confirmed progression on clb-G could cross over to next-line therapy with single-agent ibr.
Results: A total of 229 pts were randomized to ibr-G (n=113) or clb-G (n=116). Median age was 71 years (range, 40-87) and 65% of pts had high-risk genomic features. At a median follow-up of 31.3 mo, ibr-G significantly prolonged IRC-assessed PFS compared with clb-G (median not reached NR vs 19.0 mo; HR 0.231; 95% CI, 0.145-0.367; P<0.0001), with a 77% reduction in risk of progression or death (Figure 1). PFS rates at 30 mo were 79% and 31% with ibr-G and clb-G, respectively. Investigator (INV)-assessed PFS was also significantly improved with ibr-G vs clb-G (median NR vs 21.9 mo; HR 0.260; 95% CI, 0.163 to 0.415; P<0.0001). PFS benefit with ibr-G was consistent across subgroups examined. Superior PFS with ibr-G vs clb-G was also seen in the high-risk population (median NR vs 14.7 mo; HR 0.154; 95% CI, 0.087-0.270; P<0.0001), with an 85% reduction in risk of progression or death in this population (Figure 2). IRC-assessed ORR was 88% with ibr-G vs 73% with clb-G; complete response (CR/CRi) rate was also higher with ibr-G (19% vs 8%). INV-assessed ORR was 91% with ibr-G vs 81% with clb-G; CR/CRi rates were 41% and 16%, respectively. MRD was undetectable in blood and/or bone marrow (<10-4 by flow cytometry) for 35% of pts with ibr-G and 25% with clb-G. 30-mo OS rates were 86% and 85% in the ibr-G and clb-G arms, respectively, with 40% of pts randomized to clb-G receiving single-agent ibr as second-line therapy. Over a median follow-up of 31.3 mo, 4% in the ibr-G arm and 44% in the clb-G arm initiated subsequent therapy. Median treatment duration was 29.3 mo with ibr-G and 5.1 mo with clb-G. Most common (≥3%) serious adverse events (AEs) were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) with ibr-G, and infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%) with clb-G. IRRs were less frequent with ibr-G vs clb-G for both any grade (25% vs 58%) or grade ≥3 or serious IRRs (3% vs 9%). No pt discontinued G due to IRRs with ibr-G vs 7 pts (6%) with clb-G. AEs leading to discontinuation of ibr or clb occurred in 18 (16%) and 11 pts (9%), respectively; AEs leading to discontinuation of G occurred in 10 pts (9%) in ibr-G arm and 15 (13%) in clb-G arm. With ~3 yrs of follow-up, 70% of pts in the ibr-G arm remain on single-agent ibr.
Conclusions: Ibr-G resulted in superior PFS regardless of high-risk genomic features, compared with clb-G, a standard CIT regimen. Response rates and depth of remission (CR and undetectable MRD) were also higher with ibr-G. Combination therapy with ibr-G was tolerable with no new safety signals identified and represents an effective chemotherapy-free treatment option for first-line CLL/SLL including the high-risk population.
Moreno:Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Greil:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Demirkan:Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Simkovic:Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Novak:Amgen: Consultancy; Takeda: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy. Strugov:Beigene Ltd: Equity Ownership; Kite Pharma: Equity Ownership; Portola Pharmaceuticals Inc: Equity Ownership; Juno Therapeutics: Equity Ownership; TG Therapeutics Inc: Equity Ownership; Loxo Oncology Inc: Equity Ownership; Crispr Therapeutics AG: Equity Ownership; Intellia Therapeutics Inc: Equity Ownership; Editas Medicine Inc.: Equity Ownership; Ignyta Inc.: Equity Ownership; Astellas: Honoraria; AbbVie: Equity Ownership, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES; Janssen: Honoraria; ECO-SAFETY Medical Center: Employment; Aptose Biosciences Inc: Equity Ownership; Esperion Therapeutics Inc: Equity Ownership; Merck & Company: Other: TRAVEL, ACCOMODATIONS, EXPENSES. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Gribben:Roche: Honoraria; Abbvie: Honoraria; Kite: Honoraria; NIH: Research Funding; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; Acerta Pharma: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding. Hsu:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Zhou:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Clow:AbbVie: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Employment, Other: LEADERSHIP; TRAVEL, ACCOMODATIONS, EXPENSES. James:AbbVie: Equity Ownership, Other: Spouse's employment and stocks, Patents & Royalties: AbbVie Patent Applications; Pharmacyclics LLC, an AbbVie Company: Employment. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Flinn:Genentech: Research Funding; Pharmacyclics: Research Funding; Trillium: Research Funding; Curis: Research Funding; Agios: Research Funding; Forty Seven: Research Funding; Kite: Research Funding; Janssen: Research Funding; ArQule: Research Funding; Gilead: Research Funding; Calithera: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Forma: Research Funding; BeiGene: Research Funding; Merck: Research Funding; Portola: Research Funding.
Abstract
Background
Vancomycin (VAN) therapy for C. difficile infection (CDI) is effective with > 80% clinical response (CR) but is associated with 20–30% recurrence rate (rCDI). Secondary bile acids ...(2° BAs) inhibit C. difficile germination and help prevent rCDI. VAN depletes the gut microbiome decreasing the conversion of primary bile acids to 2° BAs. Ridinilazole (RDZ) is a highly selective anti-CDI, DNA-binding antibiotic in development for the treatment of CDI and prevention of rCDI.
Methods
A global, double-blinded, randomized Phase 3 trial assessed a 10-day treatment with RDZ 200 mg BID vs VAN 125 mg QID for CDI. The primary endpoint was sustained clinical response (SCR) defined as CR and no rCDI through 30 days post-end of treatment (EOT). Other endpoints included rCDI, microbiome diversity and composition, and microbiome-derived 2° BAs concentration. rCDI was defined as a new episode of diarrhea with confirmed positive free toxin test (FTT), requiring additional CDI therapy. All participants were monitored for treatment emergent adverse events (TEAE).
Results
Of the 759 patients (pts) enrolled, 745 were included in the mITT population (RDZ n=370, VAN n=375). RDZ achieved a numerically higher SCR rate than VAN (73.0% vs 70.7%) p=0.4672. RDZ resulted in a significant reduction in rCDI rate (8.1% vs 17.3%, p=0.0002) (Fig 1). In a pre-specified subpopulation, this was most notable in pts not receiving other antibiotics (rCDI 6.7% in RDZ vs 16.5% in VAN, p=0.0005). Microbiome alpha diversity was higher for RDZ vs VAN at EOT and EOT+30d (p< 0.0001 and p≤ 0.0007 respectively, Fig 2) as were relative abundance (p< 0.0001 and p=0.0203 respectively), and concentrations of 2° BAs (Fig 3). Higher microbiome diversity and concentrations of 2° BAs at EOT were associated with both lower rCDI and higher SCR rates. RDZ was well tolerated (pts with ≥ 1 TEAE: RDZ 36.4% vs VAN 35.5%, treatment discontinuation due to TEAE: RDZ 0.8% vs. VAN 2.9%).
Conclusion
RDZ was effective for sustained clinical response and safe for the treatment of patients with CDI. This was most notable in pts not receiving antibiotics. Compared to VAN, RDZ patients had faster recovery of fecal 2° BA, consistent with the preservation of microbiome diversity, resulting in a significantly lower rate of rCDI.
Disclosures
Pablo C. Okhuysen, MD, AstraZeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove: Grant/Research Support|Ferring: Advisor/Consultant|Glaxo Smith Kleine: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta: Grant/Research Support|Merck Sharp & Dohme Corp: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|Summit: Advisor/Consultant|Summit: Grant/Research Support Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Thomas J. Louie, MD, adiso therapeutics: Advisor/Consultant|adiso therapeutics: Grant/Research Support|crestone: Advisor/Consultant|crestone: Grant/Research Support|Finch: Advisor/Consultant|Finch: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Seres Therapeutics: Honoraria|summit plc: Grant/Research Support|vedanta biosciences: Advisor/Consultant|vedanta biosciences: Grant/Research Support Jianling LI, MS, Abbott: Stocks/Bonds|Abbvie: Stocks/Bonds|ALX Oncology: Stocks/Bonds|BioNTech: Stocks/Bonds|Bluebird Bio: Stocks/Bonds|Cytokinetics: Stocks/Bonds|I-Mab: Stocks/Bonds|Johnson & Johnson: Stocks/Bonds|Moderna: Stocks/Bonds|TG Therapeutics: Stocks/Bonds Esther Duperchy, PhD, Summit Plc: Employee Jose G. Montoya, MD, Summit: Honoraria|Summit: Stocks/Bonds Lori Styles, MD, Abbvie: Stocks/Bonds|Summit Therapeutics: employee|Summit Therapeutics: Stocks/Bonds Fong Clow, Sc. D, Summit Therapeutics: Employee Danelle James, MD, Summit Therapeutics: Employee.
Introduction
In 2 large phase 3 trials of patients (pts) with relapsed or refractory (R/R) CLL/SLL, single-agent ibrutinib (ibr) was superior to ofatumumab (ofa) (RESONATE; Byrd. NEJM 2013) and ibr + ...BR was superior to placebo + BR (HELIOS; Chanan-Khan. ASCO 2015). Both studies evaluated ibr in different pt populations with different relevant comparators (eg, ofa in pts who had relapsed following prior anti-CD20-based chemoimmunotherapy CIT and/or with del17p, and BR in pts eligible for CIT). In the absence of head-to-head evaluations of single-agent ibr vs BR or single-agent ibr vs ibr + BR, indirect comparisons can be used for hypothesis testing by potentially providing insights on the relative efficacy of treatments. As such, an indirect comparative analysis of data from RESONATE and HELIOS was performed. Recognizing biases inherent in cross-trial comparisons, including lack of randomization across trials and consequent differences in distributions of important confounding variables (eg, pt characteristics, prognostic factors), we used pt-level data from both studies to risk adjust for confounders using accepted multivariate statistical approaches.
Methods
In RESONATE, pts received 420 mg oral ibr daily until disease progression or unacceptable toxicity or intravenous ofa for up to 24 weeks. The primary end point was IRC-assessed PFS, with secondary end points of OS and ORR. In HELIOS, pts received BR (≤ 6 cycles) with either 420 mg oral ibr daily or placebo until disease progression or unacceptable toxicity. Pts with del17p were excluded. The primary end point was IRC-assessed PFS, with secondary end points of ORR and OS. Per protocol amendment in both studies, pts in comparator arms could switch to ibr upon IRC-confirmed progression. The current exploratory analysis was based on the latest available data from each trial (median time on study: RESONATE, 19 months; HELIOS, 17 months) using investigator assessments, but excluding del17p pts from RESONATE. Analyses were performed using data from both the overall CLL/SLL population and only the CLL pts. Separate multivariate Cox proportional hazards models were constructed for PFS and OS, including treatment and clinically relevant prognostic variables as covariates (age, gender, Rai staging, ECOG score, del11q status, refractory status, number of prior lines of therapy, bulky disease, IgVH status). Adjusted HRs and 95% CIs are presented vs single-agent ibr, along with predicted survival curves derived from the multivariate Cox regressions.
Results
RESONATE and HELIOS enrolled populations with notable differences making naïve comparison flawed. Because HELIOS enrolled only CIT-eligible pts, the trial included younger pts who had received fewer lines of therapy, as well as lower proportions of pts with purine analog refractory disease, del11q, or Rai stage 4 disease. These factors have been previously reported to influence outcomes in pts with R/R CLL/SLL and thus were included as covariates in the statistical models. Other baseline factors (gender, ECOG score, bulky disease, and IgVH status) were not notably different between the trials, but were found to impact PFS and OS and thus were included as additional covariates. In the overall CLL/SLL population, PFS and OS were comparable for single-agent ibr vs ibr + BR, and were significantly improved for single-agent ibr vs BR (Figure 1). Results for only the CLL pts were similar to those shown in Figure 1 for both PFS (ibr + BR vs single-agent ibr: 1.03 0.61-1.75, p = 0.9042; BR vs single-agent ibr: 7.52 4.72-11.99, p < 0.0001; single-agent ibr reduced the risk of progression/death by 87% vs BR) and OS (ibr + BR vs single-agent ibr: 1.20 0.59-2.43, p = 0.6197; BR vs single-agent ibr: 2.24 1.14-4.40, p = 0.0197; single-agent ibr reduced the risk of death by 55% vs BR).
Conclusions
The adjusted indirect comparisons reported here suggest superiority of single-agent ibr over BR for PFS and OS in patients with R/R CLL/SLL. The comparisons also suggest that the addition of BR to ibr did not improve PFS or OS compared with single-agent ibr. However, as median PFS has not been reached for either ibr arm, it is too early to draw firm conclusions. Longer follow-up in the ibr arms of these studies will be required to give an indication of whether CIT adds any benefit to ibrutinib for PFS and OS. Overall, these findings provide support for single-agent ibr as an appropriate choice for all pts with previously treated CLL/SLL.
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Hillmen:Roche Pharmaceuticals: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding. Fraser:Janssen: Honoraria, Research Funding, Speakers Bureau; Hoffman LaRoche: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Jones:Acerta Pharma BV: Research Funding. Rule:Roche: Consultancy, Other: Travel reimbursement; J&J: Consultancy, Other: Travel reimbursement, Research Funding; Celgene: Consultancy, Other: Travel reimbursement; Gilead: Research Funding. Dilhuydy:Roche: Honoraria, Other: Travel reimbursement; Janssen: Honoraria, Other: Travel reimbursement; Mundipharma: Honoraria. Jaeger:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cymbalista:Karyopharm: Honoraria; Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding. Sun:Janssen/J&J: Employment, Equity Ownership. Ninomoto:Pharmacyclics LLC, an AbbVie Company: Employment. Mahler:Janssen: Employment, Other: Travel reimbursement. Cheng:Pharmacyclics LLC, an AbbVie Company: Employment. Diels:Janssen: Employment. Clow:Pharmacyclics LLC, an AbbVie Company: Employment. Salman:Janssen/J&J: Employment, Equity Ownership. James:Pharmacyclics LLC, an AbbVie Company: Employment. Howes:Janssen/J&J: Employment, Equity Ownership.
The objective in this study was to characterize the pattern of the treatment-related lymphocytosis curve in chronic lymphocytic leukemia (CLL) patients treated with ibrutinib, and assess the ...relationship between the baseline factors and absolute lymphocyte counts (ALC). The PCYC-1102-CA study was a five-arm phase Ib/II open-label, nonrandomized, multicenter study in CLL/SLL. The arms and accruals were 420 and 840 mg/day treatment-naive elderly CLL/SLL (
N
= 27 and
N
= 4, respectively), 420 and 840 mg/day relapsed/refractory CLL/SLL (
N
= 27 and
N
= 34, respectively), and 420 mg/day high-risk CLL/SLL (
N
= 24). The results were generated through statistical modeling using data from a clinical trial (PCYC-1102) in five cohorts of treatment-naïve or relapsed/refractory CLL patients treated at 420 and 840 mg daily of ibrutinib. In cases in which the initial increase in ALC doubles by day 28, it takes patients longer to reach their maximum ALC when compared with those with a lower rate of increase. Our models show that all of the cohorts exhibited the same pattern of treatment-related lymphocytosis from ibrutinib, and there are no significant differences between cohorts, including no detectable dose effect. The ALC of the majority of patients return to baseline ALC values by the end of cycle 5.
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