An off-the-shelf, dual-targeted chimeric antigen receptor (CAR) T-cell approach yielded positive results in preclinical specificity, functionality, and efficacy studies, according to findings presented at the 2018 AACR Annual Meeting.

FT819, manufactured by Fate Therapeutics, is an off-the-shelf, T-cell receptor (TCR)-less CD19-targeted CAR T-cell product. “This product is responsive, cytotoxic, and specific,” noted Bob Valamehr, PhD, vice president of cancer immunotherapy at Fate Therapeutics Inc.

The hope is that this product could potentially be more accessible to patients than conventional CAR T-cell therapies, which tend to be highly personalized, time-consuming to produce, and consist of only enough cells for a single-dose treatment with variable quality.

In this new approach, investigators begin with cells from a healthy donor rather than the patient. To generate FT819, they combine reprogramming of peripheral blood-derived T cells with targeted insertion of a CD19 CAR into the T-cell receptor α (TRAC) locus under the transcriptional control of its endogenous regulatory elements to generate a single cell-derived clonal TRAC-targeted CAR-expressing master pluripotent stem cell (iPSC) line.

“Our off-the-shelf vision starts with an iPSC—a pluripotent cell that has the unique ability of unlimited self-renewal and the capacity to differentiate in to 200 cell types. Using this cell, we can effectively place multiple attributes in to a cell at the single cell level and create a master cell bank,” Valamehr explained.

In creating the master line cell, the iPSC line for the production of CAR T-cells provides distinct advantages over autologous and allogeneic approaches. In doing so, the investigators are able to produce large quantities of what Valamehr called “universal CAR19 T cells” that are not patient-restricted.

“This master cell bank, rising from a single-cell iPSC clonal population, can be plugged in to our proprietary differentiation and expansion strategy to make a mass number of T cells that are capable of multi-dose application and can basically begin to address the many challenges as discussed earlier—including creation of a homogenous product, at one time different reprogramming strategy and engineering strategy, a cost-effective process, and starting with material that is from a healthy starting source,” he added.

When using donor T cells, they can attack the patient’s tissues and organs, potentially resulting in graft-versus-host disease (GVHD); therefore, it is critical to deactivate or remove TCR.

During the stage-specific differentiation, the iPSC line dependably converted into CD34-positive cells, which were then differentiated towards CD8-positive cells with uniform CAR expression (95 +/- 5%) in the absence of TCR expression, eliminating the likelihood of GVHD. “The product is pure for CAR expression and has complete elimination of TCR. As we have been told through several clinical trials, even few cells expressing TCR can elicit GVHD. So, this pure product is now safe and highly efficacious,” Valamehr said.

In vitro functional studies showed that FT819 displayed an efficient cytotoxic T-cell response when challenged with CD19-positive tumor cells by producing cytokines (IFN-gamma, TNF-alpha, and interleukin-2) and mediators of cell death (CD107a/b, perforin, and granzyme B). FT819 was also found to be target specific by attacking only CD19-positive tumor cells and sparing CD19-negative tumor cells.

FT819 also has a second targeting receptor designed to broaden the therapy’s efficacy: a CD16 Fc receptor that can bind to tumor cells coated with antibodies, which enables the agent to be administered in combination with other proven cancer treatments, like monoclonal antibodies targeting CD20-positive tumor cells, to potentially overcome tumor antigen escape.

Also in the in vitro studies, FT819 was shown to elicit antibody-dependent cell-mediated cytotoxicity when combined with a therapeutic antibody targeting CD20, all through the expression of CD16 Fc receptor.

Valamehr noted the cells can be can be packaged, stored, and made readily available for treatment of a large number of patients.

“CAR T cells can be robustly manufactured from a multi-point engineered master iPSC line,” he added. “The master iPSC line is self-renewing and can be used repeatedly without sourcing new donor material or re-engineering cells. A single manufacturing campaign yields large quantities of CAR T cells and can be repeated in the same exact manner.”

While still in the preclinical stages, Valamehr hopes the product will be evaluated in investigational new drug studies in the coming year. “FT819 is an off-the-shelf CAR T-cell therapy with the potential to improve safety and efficacy, address antigen escape, broaden patient accessibility, and reduce cost of manufacture delivery, and really begin to make this available to the masses.”

Moderator Alice T. Shaw, MD, PhD, co-chair of the AACR Annual Meeting Clinical Trials Committee and director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center, also acknowledged how promising the product seems to treat a large number of patients.

“This is very exciting and highlights the potential utility of renewable engineered pluripotent stem cells to generate large quantities of these universal CAR T cells,” she said. “There are not only practical advantages to this approach, making the therapy more accessible to patients, but there are also important biological and therapeutic advantages in terms of our ability to modify these CAR T cells.”

Peralta E, Hardy I, Ortiz E, et al. Generation of off-the-shelf TCR-less CAR-targeted cytotoxic T cells from renewable pluripotent cells for cancer immunotherapy. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract LB-108.

Articles

An off-the-shelf, dual-targeted chimeric antigen receptor T-cell approach yielded positive results in preclinical specificity, functionality, and efficacy studies. 

FT819 Derives Renewable, Reproducible Process of CAR T-Cell Therapy

BLU-667, a next-generation tyrosine kinase inhibitor, appeared to be well-tolerated and had broad clinical benefit among patients with advanced, 

altered solid tumors who progressed on prior therapies, according to phase I study findings presented at the AACR Annual Meeting 2018, held April 14 to 18 in Chicago, Illinois.

is a rare driver of multiple, diverse tumor types including more than 60% of medullary thyroid cancers (MTCs), approximately 10% of papillary thyroid tumors, about 1% to 2% of non-small cell lung cancers (NSCLCs), and only about 1% of patients with esophageal cancer, breast cancer, melanoma, colorectal cancer, and leukemia. However, no approved therapies target RET potently and selectively.

“Precision oncology has benefitted patients with

 aberrations. Unfortunately, patients with 

-altered cancers have not benefitted from precision oncology targets to date,” Vivek Subbiah, MD, assistant professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, the University of Texas MD Anderson Cancer Center in Houston, said during the AACR Annual Meeting press conference.

“The current drugs that have been used are repurposed multi-kinase inhibitors. They have decreased activity and increased off target toxicity,” he added. “There was a need to design a selective drug for the RET pathway.”

BLU-667, currently in development by Blueprint Medicines Corporation, is a highly potent and selective oral inhibitor that targets oncogenic 

-fusions, point mutations, and resistance mutations. The preclinical and early clinical validation of the agent were also published today in 

BLU-667 was chosen for investigation because it is 100 times more selective for RET than other kinases tested, and has proved effective in stopping genetic mutations, which have been tied to resistance to multiple kinase therapy, according to an MD Anderson-issued press release.

In the open-label, first-in-human, phase I ARROW trial, Subbiah and colleagues aimed to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and anti-tumor activity of BLU-667 in advanced,

The researchers enrolled 51 patients with unresectable, advanced solid tumors which included 29 with 

 fusions, 2 with papillary thyroid cancer, and 1 with paraganglioma. Patients had a median of 1 prior anti-neoplastic therapy (range, 0-8).

The researchers administered BLU-667 orally at doses ranging from 30 mg to 400 mg daily on a 4-week cycle following a Bayesian Optimal Interval design, which allowed additional accrual to dose levels declared safe. The MTD was not reached.

BLU-667 demonstrated broad antitumor activity with a best overall response rate (ORR) of 37% (95% CI, 20%-56%) in those with

alterations who received doses ≥ 60mg and had at least 1 post-baseline response assessment (n = 30). In particular, patients with NSCLC and MTC had a best ORR of 50% and 40%, respectively. Among those with

Of the 40 evaluable patients, 1 experienced a complete response, 17 had partial responses, 20 patients achieved stable disease, and 2 patients had progressive disease.

Subbiah, who is also the Associate Medical Director of the Clinical Center for Targeted Therapy, noted these results are encouraging because this broad anti-tumor activity was seen regardless of tumor type; genomic aberration; fusion mutation; prior therapies that included immunotherapy, chemotherapy, and multi-kinase targeted therapy; and the number of prior therapies.

Rapid decline in blood and tumor biomarkers accompanied anti-tumor activity, and PK showed rapid BLU-667 absorption (Tmax 2-4 hours), long half-life (> 12 hours), and exposure (AUC and Cmax) in the expected therapeutic range based on tumor xenograft models.

BLU-667 appeared well-tolerated, with grade 1 constipation as the most common adverse event (AE; 23%). Grade 3 to 4 AEs included hypertension (8%) and neutropenia (4%), as well as increased ALT, fatigue, diarrhea, and a decrease in white blood cells (each 2%). The researchers recorded 3 dose-limiting toxicities. No grade 4 to 5 AEs occurred.

altered patients remained on treatment. “This is fantastic for a phase I study because at a lower dose level, patients may not be getting the higher doses,” Subbiah said.

The dose escalation portion of the phase I trial is open and enrolling globally. “ARROW dose escalation data validate BLU-667 as a promising precision therapy for 

Press conference moderator Louis M. Weiner, MD, co-chair of the AACR Annual Meeting Clinical Trials Committee and director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, acknowledged that the trial demonstrated empowering results, yet it also highlighted challenges associated with precision medicine.

“The trial underscores the emerging necessity of molecular profiling of cancers to identify patients who might benefit from precision targeted therapy,” he said. “The challenge associated with that is drug development is more complicated, and the molecular target is rarely found in these cancers. As a health care ecosystem, we need to find a way to find them and attack what might be considered mutational needles in a molecular haystack.”

Subbiah V, Taylor M, Lin J, et al. Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced,

altered solid tumors. Presented at: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. Abstract CT043.

BLU-667, a next-generation tyrosine kinase inhibitor, appeared to be well-tolerated and had broad clinical benefit among patients with advanced, RET-altered solid tumors who progressed on prior therapies.

BLU-667 Shows Promise for Advanced Solid Tumors With RET Alterations

Brentuximab vedotin (Adcetris) plus nivolumab (Opdivo) appeared active and well tolerated for the treatment of patients with relapsed/refractory Hodgkin lymphoma (HL), according to phase I/II study results presented at the 2017 ASH Annual Meeting.

Brentuximab vedotinan antibody-drug conjugate directed against CD30, a receptor expressed by malignant Reed-Sternberg (RS) cells present in the inflammatory/immune cell microenvironment of classical HLhas the potential to prime an antitumor immune response. This is possible through the microtubule disruption of CD30-expressing RS cells.

In conjunction, nivolumab has the ability to block PD-1 receptors, inhibit binding of PD-1 ligands, and restore an antitumor response. Therefore, targeted killing of CD30-expressin RS cells concurrent with the restoration of the immune response may improve outcomes in patients with relapsed/refractory HL. In addition, this combination regimen could elongate durability of responses following autologous stem cell transplantation (ASCT).

“Brentuximab vedotin and nivolumab are effective single-agent treatments for relapsed or refractory HL,” said Alex F. Herrera, MD, assistant professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope. “We hypothesized brentuximab vedotin in combination with nivolumab may be an active salvage regimen for relapsed or refractory HL, offering patients an alternative to traditional chemotherapy.”

In the open label, multicenter trial, researchers evaluated brentuximab vedotin in combination with nivolumab in 21-day cycles for up to 4 cycles. Patients received 1.8 mg/kg brentuximab vedotin on day 1 of cycle 1 and 3 mg/kg nivolumab on day 8 of cycle 1. They were then given the same dose of both agents on day 1 of cycles 2 through 4. After the cycle 4 assessment, patients were eligible to undergo ASCT.

Safety, adverse event (AE) incidence and severity, and complete response (CR) rate served as the primary endpoints. Secondary endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) post-ASCT, overall PFS, and biomarker analyses.

In parts 1 and 2 of the trial, 62 patients with classical HL who had relapsed or were refractory to frontline chemotherapy were enrolled. Of those enrolled, 61 patients received the combination regimen; however, only 58 patients completed treatment. Four study discontinuations were caused by patient decision (n = 2), AE (n = 1, peripheral neuropathy), and investigator decision (n = 1). Median age was 36 years, 52% were female, and 90% had received frontline chemotherapy. Overall, 45% of patients had primary refractory disease and 31% experienced relapse within 1 year of chemotherapy.

AEs were recorded from the start of treatment through 100 days after the last dose of the regimen, including the ASCT period. Sixty patients (98%) experienced AEs, including 40 who experienced grade 1/2 AEs and 19 with grade 3/4 AEs.

Infusion-related reactions (IRRs) occurred in 41% of patients during a brentuximab vedotin infusion. These IRRs occurred most frequently during cycle 2 of infusion. However, no patients discontinued treatment due to IRRs. Excluding IRRs, potential immune-related AEs occurred in 82% of patients, but again, no patients discontinued treatment as a result.

Of the 60 patients evaluable for efficacy, ORR was 83% (95% CI, 72-92), including 37 CRs (62%; 95% CI, 48-74) and 13 partial responses (22%; 95% CI, 12-34). Five patients (8%) had stable disease, 4 patients (7%) progressed on treatment, and 1 patient (2%) had clinical improvement.

At the time of analysis, 54 patients initiated ASCT. Treatment with the combination regimen did not appear to impact stem cell mobilization and collection yields or engraftment, and patients did not appear to have increased toxicity during or after the transplant period. Forty-one patients with ASCT plus the combination regimen and 16 patients with salvage therapy plus the combination regimen remain in follow-up. Median follow-up is 8 months and median DOR was not reached. Six-month PFS was 89% (95% CI, 75-95).

The researchers used peripheral blood immunophenotyping, serum cytokine/chemokine analyses, T-cell receptor sequencing, and intracellular cytokine staining to determine the combination’s effect on the immune system.

The combination increased circulating T cell numbers, and increased innate and adaptive immune activating cytokines and chemokines. The regimen also increased the ability of memory T cells to mount an immune response.

Because of this “encouraging activity” from brentuximab vedotin plus nivolumab, the combination will be further studied in multiple settings, including a pivotal phase III trial in patients with advanced HL who are ineligible for ASCT or after failure of ASCT, Herrera said.

Herrera AF, Moskowitz AJ, Bartlett NL, et al. Results from a phase I/II study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory hodgkin lymphoma. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 649.

Brentuximab vedotin (Adcetris) plus nivolumab (Opdivo) appeared active and well tolerated for the treatment of patients with relapsed/refractory Hodgkin lymphoma. 

Combination Regimen Safe, Effective as Salvage Therapy for Relapsed/Refractory Hodgkin Lymphoma

A novel approach demonstrated durable responses in the treatment of patients with smoldering multiple myeloma (SMM), according to phase II trial results presented at the 2017 ASH Annual Meeting.

A prior phase III study, conducted by the Spanish Myeloma Group, showed that treatment with lenalidomide (Revlimid) and dexamethasone early in a treatment course for patients with SMM, an asymptomatic plasma cell disorder that includes patients with a different risk for progression to multiple myelomas, may significantly improve progression-free survival (PFS).

“This curative approach for high-risk SMM seems to be encouraging,” said Maria-Victoria Mateos, MD, PhD, University Hospital of Salamanca in Spain. She presented results from a single-arm, phase II trial during an oral abstract session Sunday.

The single-arm, phase II trial evaluated a strategy using induction therapy with carfilzomib (Kyprolis), lenalidomide, and dexamethasone followed by high-dose therapy and autologous stem cell transplantation (HDT-ASCT), consolidation therapy and then maintenance therapy with lenalidomide and dexamethasone.

Ninety patients (median age, 59 years) were recruited from June 2015 to June 2017. All patients were at high risk for progression, defined as having a risk of 50% or more at 2 years, according to Mayo (n = 19), Spanish (n = 47) or both (n = 24) risk models.

Seventy-one patients underwent 6 4-week cycles of induction therapy. Patients received 36 mg/m2 carfilzomib twice weekly, 25 mg lenalidomide on days 1 through 21, and 40 mg dexamethasone weekly. Forty-two patients moved on to recieve 200 mg/m2 melphalan followed by ASCT for intensification therapy, and again 3 months later.

Next, 35 patients received two consolidation cycles of carfilzomib, lenalidomide and dexamethasone. Twenty-nine of those patients went to receive maintenance therapy with 10 mg lenalidomide on days 1 through 21, plus 20 mg dexamethasone weekly for up to 2 years.

Flow minimal residual disease (MRD)-negative rate after induction, HDT-ASCT, consolidation, maintenance, and at 3 and 5 years post maintenance served as the primary objective. Secondary endpoints included response rates, time-to-progression, PFS, overall survival, and safety and tolerability.

After a median follow-up of 10 months, PFS and OS were 94% and 98%, respectively, at 28 months.

After induction, all patients achieved an overall response, including 21 stringent complete responses (CRs; 30%), 11 CRs (13%), 27 very good partial responses (VGPRs; 38%), and 12 partial responses (PRs; 17%). Mateos noted that 2 patients achieved CR, but relapsed before the end of induction and one patient withdrew.

In addition, 31% of patients were MRD-negative, an improvement of 26% in the quality of response over treatment. Grade 3/4 adverse events (AEs) included infections (9%), skin rash (8%), neutropenia (4%), and thrombocytopenia (2%). Investigators observed 2 cardiovascular events, 1 grade 1 atrial fibrillation and 1 grade 1 cardiac failure. Two patients reported grade 2 arterial hypertension.

All 42 patients achieved an overall response following HDT-ASCT including 22 stringent CRs (52%), 2 CRs (5%), 12 VGPRs (29%), and 6 PRs (14%). Half of those patients were MRD-negative, an improvement of 47% in the quality of response over treatment. Peripheral blood stem cell collection was successful in all but 1 patient, with a median number of CD34+ cells collected of 6.79 x 106/Kg. Engraftment occurred in all patients, and the median number of CD34+ infused was 3.29 x 106/Kg. No patient discontinued during treatment or in the 100 days post-HDT-ASCT.

All patients who completed the 2 planned consolidation cycles had an overall response, including 24 stringent CRs (69%), 2 CRs (6%), 7 VGPRs (20%), and 2 PRs (6%). Sixty percent of these patients were MRD-negative, an improvement of 62% in the quality of response over treatment. No patients discontinued consolidation. During consolidation, 2 patients developed grade 3/4 neutropenia.

All patients in the maintenance group achieved an overall response, including 24 stringent CRs (83%), 2 CRs (7%), 2 VGPRs (7%), and 1 PR (3%). MRD-negative status was unavailable. No patients discontinued maintenance therapy. Two patients developed grade 3/4 neutropenia.

Overall, treatment-related AEs included pneumoniae (n = 1), respiratory infection (n = 1), infections (n = 2), enterocolitis (n = 1), cutaneous exantema (n = 1), decapited meningitis (n = 1), and massive ischemic stroke (n = 1). Neutropenia, infections and skin rash were the causes for dose reductions in treatment using lenalidomide (n = 19), and dexamethasone (n = 10).

“The safety profile is acceptable,” Mateos said. “And although infections are the most frequent treatment-related AEs, most were mild and manageable.”

Mateos MV, Lopez JM, Rodriguez-Otero P, et al. Curative strategy for high-risk smoldering myeloma (GEM-CESAR): Carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed By HDT-ASCT, consolidation with KRd and maintenance with Rd. Presented at: Annual ASH Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 402.

A novel approach demonstrated durable responses in the treatment of patients with smoldering multiple myeloma, according to results from a single-arm, phase II trial.

Curative Approach Improves Responses in Patients With Smoldering Multiple Myeloma 

Treatment using BLU-285 (Avapritinib) induced clinically significant activity in patients with an advanced or aggressive form of systemic mastocytosis (ASM), a rare blood disorder that originates in mast cells, according to data from an ongoing phase I trial.

The results presented at the 2017 ASH Annual Meeting also showed the agent was well tolerated among patients.

Of the 18 measurable patients criteria, 72% (n = 13) achieved an overall response, including 2 complete responses and 8 partial responses Three patients showed clinical improvement, and 5 patients had stable disease. Lastly, all patients had disease control. Of these 18 patients, 17 remain on treatment.

Mast cells typically help protect the body from infection, however, systemic mastocytosis (SM) can occur when mast cells start to grow uncontrollably. The KIT D816V mutation is a common disease driver for ASM, SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL)all of which have debilitating symptoms, increased organ dysfunction and damage, and decreased overall survival. The mutation is found in approximately 90% to 95% of patients with SM.

Midostaurin (Rydapt), a multikinase inhibitor with a broad inhibitory spectrum that includes KIT D816V, is the only currently approved agent to treat advanced or aggressive SM. Unfortunately, existing treatments for the disease, including midostaurin, are limited in efficacy.

“Midostaurin is finally catching on,” said Daniel J. DeAngelo, MD, PhD, associate professor of medicine at Harvard Medical School and a member of the adult leukemia program at the Dana-Farber Cancer Institute in Boston. “It is not a trivial agent to administer, it does have a good response rate, it improves symptoms, but we do not see a lot of complete remissions.”

BLU-285 was specifically designed to treat SM as a highly potent and specific oral inhibitor of KIT D816V. In part 1 of the ongoing, phase I study, researchers aimed to establish a maximum tolerated dose (MTD), a recommended dose for phase II of the study (RP2D), and safety. Secondary study objectives included pharmacokinetics (PK) and preliminary anti-neoplastic activity of the agent.

Of 32 patients including 17 with ASM, 9 with SM-AHN, 3 with MCL; and 3 with other D816V-mutant hematologic neoplasms70% had received at least 1 prior anti-neoplastic therapy, including cladribine (n = 6), imatinib (Gleevec; n = 4), interferon-alfa (n = 4), midostaurin (n = 4), and 5-azacitidine (n = 3).

Seven cohorts of patients received once-daily BLU-285, ranging from doses of 30 mg to 400 mg, on a 4-week cycle following part 1/part 2 of the study, a 3+3 escalation/dose expansion. This 2-part process included the following:

Dosing began at 30 mg per day and increased in a stepwise fashion to 400 mg per day

The first 3 patients enrolled received a low dose of the study drug and were monitored for adverse effects

If no adverse events were seen, the next three patients received a higher dose

This continued until dose escalation was stopped when adverse events were seen in 30% of the patients treated

DeAngelo said the agent demonstrated significant clinical activity across all dose levels, including rapid and durable reductions in mast cell burden, from a median burden of 20 at baseline to 5 at best response, and in D816V mutant allele fraction, from 4.5% at baseline to 1.1% at best response. These reductions were durable, including 7 that lasted for 1 year or more, and occurred regardless of ASM subtype, prior therapy, concomitant mutations, and performance status.

Of note, 2 patients with MCL that progressed on midostaurin and 2 patients with ASM who were intolerant to midostaurin had reductions in mast cell burden, and all four remain on therapy at 5, 12, 7, and 14 months, respectively.

The most common adverse events (AEs) of any grade included periorbital edema (59%), fatigue (41%), peripheral edema (34%), nausea (28%), anemia (28%), thrombocytopenia (28%), abdominal pain (22%), diarrhea (22%), respiratory tract infection (22%), dizziness (22%), headache (22%), and neutropenia (13%).

Sixteen patients experienced grade ≥3 treatment-related AEs, including neutropenia (13%), anemia (7%), and periorbital edema (7%).

Thirty of 32 patients enrolled remain on treatment, with a median duration of 9 months. The two patients who discontinued treatment were not because of drug-related AEs. The researchers observed one dose-limiting toxicity at 60 mg, but MTD was not reached.

Based on these results, DeAngelo is hopeful that success found with BLU-125 will lead to more diagnoses of SM.

“BLU-285 has been a wonderful success in terms of getting a majority of patients in complete and partial remissions,” he said. “So, as this evolves, having better targeted agents, will improve the outcome. The second thing that it does, once you have successful therapeutic options for patients, then you can pick up and diagnose more patients. It is impressive how many newly diagnosed patients were seen that were misdiagnosed previously.”

Based on safety profile, PK, and anti-tumor activity, the researchers selected 300 mg as the RP2D. As of Nov. 27, 2017, 7 patients were enrolled in part 2 of the study, designed to evaluate dose expansion in additional patients, including 15 with ASM, 15 with SM-AHN, and 5 with MCL.

The researchers are currently planning a phase II study designed to assess the effectiveness of a once-daily dose of 300 mg BLU-285 in patients with ASM. In addition, DeAngelo said researchers are evaluating the agent for the treatment of indolent SM and smoldering SM.

DeAngelo DJ, Quiery AT, Radia D, et al Clinical activity in a phase I study of blu-285, a potent, highly-selective inhibitor of kit D816V in advanced systemic mastocytosis (AdvSM). Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 2.

Treatment using BLU-285 (Avapritinib) induced clinically significant activity in patients with an advanced or aggressive form of systemic mastocytosis, according to data from an ongoing phase I trial.

Alternative Agent Shows Clinical Activity in Patients With Advanced Systemic Mastocytosis

Treatment using oral rivaroxaban (Xarelto) reduced venous thromboembolism (VTE) recurrence among patients with cancer, according to results from the select-d trial.

Study results, presented at the 2017 ASH Annual Meeting and Exposition, also showed an increase in clinically relevant non-major bleeds (CRNMB) among patients treated with rivaroxaban, suggesting this regimen may only be a safe and beneficial alternative in select patients.

Dalteparin (Fragmin), a low molecular weight heparin, is the standard of care for the extended treatment and prevention of acute VTE recurrence in patients with cancer. Rivaroxaban, a direct oral anticoagulant (DOAC), is a highly selective direct Factor Xa inhibitor with oral bioavailability, and may be another treatment option for this patient population.

“Clinicians are already adopting DOACs into practice for these patients,” Annie Young, PhD, Warwick Medical School, University of Warwick, Coventry in the United Kingdom, said in an ASH press release. However, comparisons between the two regimens are limited.

Young and colleagues conducted the prospective, randomized, open label, multicenter pilot trial, designed to compare dalteparin, administered subcutaneously, with rivaroxaban for the treatment of VTE in 406 patients with cancer, including those with symptomatic or incidental pulmonary embolism (iPE) or symptomatic lower extremity proximal deep vein thrombosis (DVT).

In month 1, patients in the dalteparin arm received 200 IU/kg daily followed by 150 IU/kg in months 2 through 6. Patients in the rivaroxaban arm were administered 15 mg twice daily for 3 weeks followed by 20 mg once daily for 6 months in total. After 6 months of trial treatment, DVT patients who were residual vein thrombosis (RVT)-positive and patients with PE at presentation, could be randomized to placebo or rivaroxaban for an additional 6 months.

The initial randomization included 530 patients, of which 150 patients remained in each arm of the second randomization to assess the duration of anticoagulation. The trial sample size was reduced when the second randomization closed due to a high attrition rate.

A revised sample size of 203 patients in each arm comprised the evaluation for the trial’s primary endpointVTE recurrence. Secondary endpoints included major bleeds and clinically relevant non-major bleeds—including overt bleeds resulting in unscheduled contact with a physician or interruption or discontinuation of study drug&mdash;acceptability, survival, and health economics.

Patients were a median age of 67 years, of which more than half were males (53%) and majority were white (95%). They presented with either early or locally advanced disease (n = 156; 38%), metastatic disease (n = 240; 59%); or hematologic malignancies (n = 10; 3%). Patients also presented with iPE (n = 214; 53%), or had symptomatic PE or DVT (n = 192; 47%). Of the 280 patients who were receiving anticancer treatment at the time of the VTE, most were receiving chemotherapy (n = 232; 83%) or targeted therapy (n = 41; 15%).

The rivaroxaban arm (4%; 95% CI, 2-9) induced lower rates of VTE recurrence compared with the dalteparin arm (11%; 95% CI, 7-17). Major bleeds appeared similar between arms, with 6 bleeds from 6 patients who received dalteparin (3%; 95% CI, 1-6) and 9 bleeds from 8 patients who received rivaroxaban (4%; 95% CI, 2-8).

However, more CRNMBs occurred in the rivaroxaban arm, totaling 28 bleeds from 27 patients (13%; 95% CI, 9-19) compared with 5 bleeds in 5 patients who received dalteparin (2%; 95% CI, 1-6). Overall, 11 patients (5%; 95% CI, 3-9) in the dalteparin arm had bleeds categorized as either major bleeds or CRNMBs compared with 34 patients (17%; 95% CI, 12-22) in the rivaroxaban arm.

The researchers are conducting further analyses to try to understand factors that may have contributed to this difference, according to an ASH press release.

“Now [clinicians] have data from this study to indicate that DOACs are potentially safe in cancer patients,” Young said in the press release. “We need to be looking at different groups of people and different types of bleeds in more detail, so that we can choose the best treatment for each patient.”

In addition, a total of 208 patients completed 6 months of treatment, including 100 patients who received dalteparin (52%) and 108 patients who were on rivaroxaban (55%). At 6 months, the rivaroxaban arm (74%; 95% CI, 68-80) demonstrated superior overall survival compared with the dalteparin arm (70%; 95% CI, 63-76).

In the second randomization, only 92 patients of the required 300 were recruited, including 82 PEs and 10 DVTs. Patients did not continue to the second randomization as a result of death or withdrawal (50%); being RVT-negative (12%); failing the other eligibility criteria (24%); or declining to participate in randomization (14%).

Young A, Marshall A, Thirlwall J, et al. Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: results of the select-d pilot trial. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta. Abstract 625. [ash.confex.com/ash/2017/webprogram/Paper104979.html]

Direct Oral Anticoagulant Prevents VTE Recurrence in Select Patients With Cancer

A mix of traditional and customized acupuncture techniques proved effective in reducing pain and stiffness associated with aromatase inhibitor (AI) therapy in women with early-stage breast cancer, according to data from a randomized phase III trial presented at the 2017 San Antonio Breast Cancer Symposium (SABCS).

Investigators said a 12-week intervention program demonstrated the value of the therapy to help relieve symptoms that may cause patients to skip or stop treatments. “We have heard throughout this conference about the efficacy of AIs for women with hormone-sensitive breast cancer. It works both in the adjuvant setting in women with metastatic disease, and for the prevention of breast cancer.” said Dawn L. Hershman, MD, MS, leader of the Breast Cancer Program at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Columbia University Medical Center.

“But we also know that it doesn’t work if you don’t take it, and noncompliance is a major problem amongst women taking hormonal therapy,” Hershman said in discussing the research team’s findings during an SABCS press briefing.

Hershman acknowledged that noncompliance can be multifactorial, but one of the main reasons patients discontinue treatment is because of adverse effects and, in particular, joint pain and stiffness. “[Therefore,] we were interested in a nonpharmacologic modality for assessing whether or not we could control these symptoms.”

Small studies have suggested acupuncture may be beneficial in treating AI-associated arthralgia; however, these findings are not consistent across all trials. To test this theory across multiple measures, the researchers conducted the multicenter, randomized phase III trial designed to evaluate the efficacy of acupuncture in reducing AI-related joint symptoms over a 24-week period.

Patients reported their pain before, during, and after acupuncture or no treatment using the Brief Pain Inventory (BPI)-Short Form, a self-administered questionnaire of 14 items, to evaluate the severity of pain on a scale of 0 to 10, with higher scores indicating more pain and an increased impact on daily functioning.

To be eligible, women were required to have hormone receptor-positive, stage I to III breast cancer; be taking a third-generation AI for at least 30 days; report a score of 3 or more of BPI worst pain; have symptoms that started or progressed since starting AI therapy; have received no opioids, corticosteroids, or alternative/physical therapy for joint pain for 28 days prior to registration; and have had no prior acupuncture treatment for AI-associated joint pain.

Researchers randomized 226 patients 2:1:1 to the following treatment arms:

True acupuncture: standard traditional Chinese medicine point prescription, a 30- to 45-minute session including a full body, auricular, and joint-specific acupuncture protocol tailored to the most painful joints (n = 110)

Sham acupuncture: shallow needle insertion with thin, short needles at 4 standardized non-acupuncture points (n = 59)

Waitlist control: patients were under the impression they would receive true acupuncture following the 24-week trial (n = 57).

Improved joint pain score after 6 weeks served as the primary endpoint. The researchers also evaluated maintenance acupuncture efficacy from weeks 6 through 12, followed by an additional 12-week follow-up. True acupuncture and sham treatments included twice-weekly sessions for 6 weeks followed by 1 session per week for 6 more weeks.

Patients were a median 60.7 years of age, and had been receiving AI therapy for a median of 1.1 years. Forty-four women previously received acupuncture therapy for other conditions (19%). At baseline, women reported BPI worst pain scores of 6.84, 6.55, and 6.48 in the true, sham, and waitlist arms, respectively.

After 6 weeks of treatment, mean BPI worst pain scores were 0.92 points lower in the true acupuncture arm (95% CI, 0.20-1.65; 

= .01) compared with the sham arm, and 0.96 points lower than the waitlist control arm (95% CI, 0.24-1.67;

Additionally, the true acupuncture arm demonstrated a greater proportion of patients reporting clinically meaningful reductions in BPI worst pain of 2 points or more (58%), compared with the sham (31%;

 < .004). According to a linear mixed model, these data remained statistically significant at 24 weeks.

The true acupuncture arm also outperformed the sham and waitlist arms in additional 6-week endpoints, including more favorable BPI scores for average pain, pain interference, pain severity, and worse stiffness. Similarly, these results were maintained after 24 weeks according to a linear mixed model.

“We have shown consistently, with multiple measures assessing pain and stiffness, that true acupuncture generated better outcomes than either control group in a large multicenter randomized controlled trial,” Hershman said. “And transitioning from twice-a-week to once-a-week acupuncture maintained the effect of the intervention.”

Grade 1 bruising appeared to be the only significant adverse event reported among true (47%) and sham acupuncture patients (25%; P = .01).

“Acupuncture provides a nonpharmacologic option that can improve symptoms and possibly increase AI adherence as well as subsequent breast cancer outcomes,” Hershman said. “For patients who are reluctant to take a prescription medication that can result in other side effects, acupuncture provides a safe and effective alternative. Identification of nonopioid options for pain control is a public health priority.”

Hershman also noted the added benefits derived from the cost of the 12-week, 18-session intervention, which amounted to approximately $1250 ($65-$75 per session).

“We feel there is now sufficient evidence to support insurance coverage of acupuncture for AI arthralgia, “she said.

Hershman DL, Unger JM, Greenlee H, et al. Randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in women with early stage breast cancer (S1200). Presented at: 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio, TX. Abstract GS4-04. abstracts2view.com/sabcs/view.php?nu=SABCS17L_503&terms=

A mix of traditional and customized acupuncture techniques proved effective in reducing pain and stiffness associated with aromatase inhibitor (AI) therapy in women with early-stage breast cancer.

Acupuncture Reduces AI-Associated Joint Pain in Women with Breast Cancer

Shortening the intervals between chemotherapy cycles or administering the drugs sequentially reduced early-stage breast cancer recurrence and mortality compared with standard dosing techniques, according to meta-analysis results presented at the 2017 San Antonio Breast Cancer Symposium.

The 2 most commonly used chemotherapy regimens, anthracycline- and taxane-based combinations, are proven to reduce mortality among women with early breast cancer by one-third. However, pivotal trials have demonstrated there may be an added benefit from dose intensification.

“We are still trying to find ways in improving how we deliver this chemotherapy,” said Richard Gray, MSc, professor of medical statistics in the Nuffield Department of Population Health at University of Oxford in the United Kingdom. “The rationale for this is if you look at computer models about how cancer cells get knocked back by chemotherapy and then regrow again, it seems if you increase dose intensity, you might be more likely to eradicate more cancer cells.” Gray and colleagues collected data from the Early Breast Cancer Clinical Trialists' Collaborative Group (EBCTCG), a worldwide collaboration designed to assess the long-term benefits and adverse effects associated with a variety of treatment options for patients with early-stage breast cancer. In particular, the researchers focused on whether increasing the dose intensity of chemotherapy would induce superior outcomes compared with standard chemotherapy regimens. Dose intensification trials used the same chemotherapy agents at the same doses as in standard regimens but patients received the drugs every 2 weeks versus every 3 weeks, resulting in an average weekly dose that is 1.5 times higher. Additionally, doses may be intensified by administering chemotherapy in sequence rather than concurrently.

Individualized patient data were analyzed from 25 trials, including the following:

Seven randomized trials, designed to test chemotherapy given every 2 weeks compared with every 3 weeks (n = 10,004)

Nine randomized trials, which tested sequential versus concurrent anthracycline- and taxane-based chemotherapies (n = 11,533)

The researchers evaluated reductions in disease recurrence and morality, as well as safety.

Patients who received chemotherapy every 2 weeks appeared 17% less likely to experience disease recurrence (rate ratio [RR], 0.83; 95% CI, 0.76-0.91; P = .00004), with a 14% reduction in the risk of death from breast cancer within 10 years (RR, 0.86; 95% CI, 0.77-0.95; P = .004), compared with patients who received the same treatment every 3 weeks.

Similarly, patients who received sequential chemotherapy every 3 weeks demonstrated a 13% reduction in the risk for disease recurrence (RR, 0.87; 95%CI, 0.80-0,94; P = 0006), and were 11% less likely to die from breast cancer within 10 years (RR, 0.89; 95% CI, 0.80-0.99; P = .03) compared with patients who were treated with concurrent therapy ever 3 weeks.

In a pooled analysis of the 25 identified trials, patients who received dose-intensification therapy showed a 15% reduction in the risk for disease recurrence (RR, 0.85; 95% CI, 0.81-0.89; P <.00001) and a 13% reduction in the risk for breast cancer mortality (RR, 0.87; 95%CI, 0.82-0.92; P <.00001) compared with those who received standard therapy.

“This reduction [in mortality] may seem a very marginal difference, but when you think that we have already made a lot of improvements with chemotherapy … you can then [administer] dose intensification, and a one-third reduction comes to almost half a reduction in breast cancer mortality,” Gray said. “These increments have made a really big difference in breast cancer survival by identifying little ways of improving what we are doing already.”

“Whichever way these trials are achieving dose intensification they seem to be finding benefit in fewer recurrences,” Gray added. “This is quite remarkable how consistent all of these different approaches work in showing fewer recurrences and breast cancer mortalities.”

Despite concerns about safety, the researchers also found few additional adverse events among those who received dose-intense treatments, including fewer patients who died from non-breast cancer causes.

Virginia G. Kaklamani, MD, co-director of the symposium and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, commended these findings, noting the win-win therapeutic approach. “The beauty of these approaches is [we are using the] exact same drugs and similar doses. It is just the schedule that changes,” she said. “What is interesting is we used to give chemotherapy over 6 months and with this approach we can give it over 4 months. The patients prefer it, and the toxicity can be less. So, everyone wins here.”

Moving forward, Gray noted the need for more trials to be conducted.

“The problem is, often, that we have not looked well enough at simple questions on how long to give chemotherapy, which is really important for women to get more benefit without extra toxicity,” he said. “What we need is more trials to test simple concepts, very simple bread-and- butter questions that should be addressed more often in clinical trials.”

Gray R, Bradley R, Braybrooke J, et al; for the EBCTCG. Increasing the dose density of adjuvant chemotherapy by shortening intervals between courses or by sequential drug administration significantly reduces both disease recurrence and breast cancer mortality: An EBCTCG meta-analysis of 21,000 women in 16 randomised trials. Presented at: 2017 San Antonio Breast Cancer Symposium; Dec. 5-9; Atlanta. Abstract GS1-01. abstracts2view.com/sabcs/view.php?nu=SABCS17L_1396&terms=

Shortening the intervals between chemotherapy cycles or administering the drugs sequentially reduced early-stage breast cancer recurrence and mortality compared with standard dosing techniques.

Kristie L. Kahl