On December 7, 2018 Johnson & Johnson Janssen pharmaceutical companies reported new results from three important studies on IMBRUVICA (ibrutinib) in chronic lymphocytic leukemia (CLL), a form of difficult blood cancer treatment as well as the most common type of leukemia in adults (Press release, Johnson & Johnson, DEC 7, 2018, View Source [SID1234531954]). 1 The results were presented during the 60th annual congress of the American Society of Hematology (ASH) (Free ASH Whitepaper) in San Diego, California.

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The results of the Phase 3 study (E1912) sponsored by the National Cancer Institute (NCI) and led by the ECOG-ACRIN Cancer Research Group (ECOG-ACRIN) were presented during the oral session dedicated to abstracts late breakers. The study evaluated ibrutinib in combination with rituximab compared to a chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated CLL patients younger than 70 years. Following a nearly 3-year follow-up, these data showed that the combination of ibrutinib plus rituximab significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to FCR. 2

Data from the iLLUMINATE phase 3 study (PCYC-1130) were also presented during an oral session, with concurrent publication in The Lancet Oncology . The results show that the combination of ibrutinib and obinutuzumab significantly improves PFS compared to chlorambucil and obinutuzumab in recently diagnosed CLL patients. 3 These data recently supported the submission of a Type 2 variation application to the European Medicines Agency (EMA) to request authorization for the extended use of ibrutinib in combination with obinutuzumab in previously untreated CLL adults.

Data from the 1b / 2 hybridutinib study and the related extension study (PCYC-1102, PCYC-1103) with a follow-up of up to seven years on newly diagnosed relapsed / refractory (R / R) CLL patients they also demonstrated long-term and long-term survival benefits following monotherapy treatment, and constitute the longest follow-up for a Bruton tyrosine kinase (BTK) inhibitor in CLL. 4

"The results of iLLUMINATE and ECOG-ACRIN studies demonstrate an extremely prolonged progression-free survival for the relative combinations based on ibrutinib compared to commonly used chemo-immunotherapy regimens," said Dr. Carol Moreno, Hematology Consultant at Hospital de the Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, ​​Barcelona, ​​Spain. "These non-chemotherapeutic regimens are a step forward in assessing how patients are treated, including the younger ones and with high-risk CLL, and offer the potential to resolve the compromise between efficacy and toxicity for patients."

"The data presented at the INA congress provide a further and convincing evidence of the clinical benefits that ibrutinib can offer to patients across the spectrum of CLL management." Long-term data are also promising in terms of long-term found for patients, "said Dr. Catherine Taylor, head of the hematology area for the EMEA region (Europe, Middle East and Africa) of Janssen-Cilag Limited. "We continue to study the full potential of ibrutinib with a comprehensive clinical development program, to improve results and modify the consequences of diagnosing blood cancer for patients."

Ibrutinib, a first class BTK inhibitor, is developed and marketed jointly by Janssen Biotech, Inc., and Pharmacyclics LLC, an AbbVie company.

Results of the Randomized Phase 3 Study on Hybridinib (PCI-32765) Therapy vs. FCR Chemo-Immunotherapy in Untreated Young CLL Patients: an ECOG-ACRIN Cancer Research Group Study (E1912) ( Abstract No. LBA-4 )

The partial analysis, with a median follow-up of 33.4 months, was performed on 77 PFS events and 14 deaths. Ibrutinib plus rituximab significantly improved PFS compared to FCR (HR: 0.352; [CI, confidence interval] 95%: 0.223-0.558; P <0.0001); the predetermined limit for PFS has been exceeded. Also the treatment arm with ibrutinib plus rituximab showed an improvement in OS (HR: 0.168; 95% CI: 0.053-0.538; p = 0.0003, predetermined limit for superiority p = 0.0005). 2

In a subgroup of PFS analyzes, ibrutinib plus rituximab showed prolongation of PFS regardless of age, gender, general condition, disease stage or presence / absence of cytogenetic abnormality deletion 11q23. With the current follow-up also ibrutinib plus rituximab was superior to FCR in patients without IgHV mutation (HR: 0.262; CI 95%: 0.137-0.498; p <0.0001), but not in patients with IGHV mutation (HR: 0.435; 95% CI: 0.140-0.1350; p = 0.07). 2

Treatment-related grade 3 or 4 adverse AE events (AEs) were observed in 58% of patients treated with ibrutinib plus rituximab and in 72% of patients treated with FCR (p = 0.0042). The FCR arm was more frequently associated with grade 3 and 4 neutropenia (FCR: 44% compared to ibrutinib plus rituximab: 23%; p <0.0001) and infectious complications (FCR: 17.7% compared to rituximab: 7.1%, p <0.0001). 2

Results from the iLLUMINATED phase 3 study ( abstract No. 691 )

At a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged the PFS assessed by an independent review board (IRC) compared to chlorambucil plus obinutuzumab (median not achieved [NR] vs. 19.0 months; 0.231; 95% CI: 0.145-0.367; P <0.0001), with a 77% reduction in risk of progression or death. 3

Higher PFS values ​​in the armutinib plus obinutuzumab than the chlorambucil plus obinutuzumab arm were also observed in the high-risk population, including cases with IGHV, del11q, del17p and / or TP53 mutation, with 85% reduction in risk progression or death (median NR vs. 14.7 months; HR 0.154; 95% CI: 0.087-0.270; P <0.0001). 5The overall response rate (ORR) assessed by the IRC was also higher for the hybridutinib arm plus obinutuzumab than the chlorambucil plus obinutuzumab arm (88% vs. 73%); also the complete response rates (CR) / complete response with incomplete recovery of the blood count (CRi) were higher, respectively 19% compared to 8%. The minimal residual disease (MRD) was not detectable in the blood and / or bone marrow (<10 -4flow cytometry) in 35% of patients treated with ibrutinib plus obinutuzumab compared to 25% of patients treated with chlorambucil plus obinutuzumab. The 30-month OS rates were 86% for the hybridutinib plus obinutuzumab arm compared to 85% of the most obinutuzumab chlorambucil arm. 3

The most common grade 3 or higher adverse AE (AE) events in the most obinutuzumab-hybridutib arm compared to the most obinutuzumab-chlorambucil arm were: neutropenia (36% vs. 46%), thrombocytopenia (19% vs. 10%), pneumonia (7 % vs. 4%), atrial fibrillation (5% vs. 0%), febrile neutropenia (4% vs. 6%), anemia (4% vs. 8%) and infusion-related reactions (IRR; 2% vs 8%). 5No patients discontinued obinutuzumab due to IRR in the armutinib plus obinutuzumab arm compared to the chlorambucil plus obinutuzumab arm (6%). The EAs led to the interruption of ibrutinib in 16% of patients and led to the interruption of chlorambucil in 9% of patients. The AEs led to the discontinuation of obinutuzumab in the hybridutinib arm plus obinutuzumab (9%) and in the chlorambucil arm plus obinutuzumab (13%). At a follow-up of approximately three years, 70% of patients in the hybridutinib arm plus obinutuzumab continue to be treated with ibrutinib monotherapy. 3

Results from the follow-up up to seven years of the PCYC-1102 phase 1b / 2 study and its extension, PCYC-1103 ( abstract No. 3133 )

The results of these studies showed a lasting efficacy of ibrutinib in newly diagnosed CLL R / R patients. Long-term data showed sustained rates of PFS and OS. The estimated seven-year PFS rates were 80% for newly diagnosed patients and 32% for R / R patients. In particular, the administration of ibrutinib in the first lines of therapy has led to an improvement in PFS for R / R patients. 4

The ORR value was 89% for all patients (CR, 15%), with similar rates in newly diagnosed patients (87% [CR, 32%]) and in CLL R / R patients (89% [ CR, 10%]). Median response duration (DOR) was NR (CI 95%: 0 + -85 +) for newly diagnosed CLL patients and 57 months (CI 95%: 0 + -85 +) for CLL patients R / R. 6 Median PFS was NR (CI 95%: non-evaluable [NE], NE) for newly diagnosed CLL patients and was 51 months (95% CI: 37-70) for CLL R / R patients. 4.6 The median OS was NR for newly diagnosed patients (95% CI: 80-NE) or CLL R / R patients (95% CI: 63-NE), with estimated OS rates at seven years 75% and 52% respectively. 4

Grade 3 or higher adverse events were reported in 74% of newly diagnosed patients and 89% of CLL R / R patients. Among the most common grade 3 or higher adverse events that occurred during treatment were hypertension (new diagnosis, 32%, R / R, 26%), diarrhea (new diagnosis, 16%, R / R, 4%) and hyponatraemia (new diagnosis, 10%, R / R, 0%). Severe hemorrhages of grade 3 or higher atrial fibrillation, thrombocytopenia, anemia and arthralgia have been observed in 11% or less of newly diagnosed and R / R patients. In addition, infections (newly diagnosed, 23%; R / R, 55%) occurred in CLL R / R patients. 6No new or unexpected adverse events were observed, and the frequency of most grade 3 or higher adverse events and serious adverse events decreased over time, with the exception of hypertension. 6

#END#

Information on the ECOG-ACRIN E1912 study

The phase 3 study (E1912) evaluated previously untreated CLL patients aged up to 70 years, randomized to ibrutinib (420 mg / day until disease progression) and rituximab (50 mg / m 2 on day 1 of cycle 2 325 mg / m 2 on day 2 of cycle 2, 500 mg / m 2 on day 1 of cycles 3-7) (n = 354) or six doses of fludarabine for intravenous (25 mg / m 2 ) and cyclophosphamide (250 mg / m 2 ) days 1-3 with rituximab (50 mg / m 2 on day 1 of cycle 1; 325 mg / m 2 on day 2 of cycle 1; 500 mg / m 2day 1 of cycles 2-6) every 28 days (n = 175). The primary endpoint was PFS, with a secondary endpoint of OS. 2

The federally funded study was designed by researchers with ECOG-ACRIN and was conducted through the National Clinical Trials Network of NCI. Pharmacyclics LLC provided hybridutinib under a research and development cooperation agreement with NCI and a separate agreement with ECOG-ACRIN.

Information on the iLLUMINATE study

iLLUMINATE ( PCYC-1130 ) evaluated newly diagnosed CLL patients randomized for continuous administration of hybrid 420 mg once daily until disease progression or unacceptable toxicity, in combination with obinutuzumab 1000 mg intravenously over 6 cycles (n = 113); or chlorambucil on days 1 and 15 of each cycle plus obinutuzumab 1000 mg intravenously over 6 cycles (n = 116). The median age of patients was 71 years and 65% of patients had high-risk genomic characteristics. The primary endpoint was the PFS, assessed by an independent review board. Secondary endpoints included PFS in a high-risk population, undetectable MRD, ORR, OS, and safety. 3

Information on PCYC-1102 and PCYC-1103

With a follow-up of up to a maximum of 7 years, studies ( PCYC-1102 phase 1b / 2 and its extension, PCYC-1103 ) evaluated newly diagnosed CLL R / R patients (n = 132; diagnosis = 31, R / R = 101), including those with high-risk characteristics, who received either ibrutinib 420 mg or 840 mg once daily until disease progression or unacceptable toxicity. At the time of the cutoff, 55% of newly diagnosed patients and 21% of R / R patients continued treatment with ibrutinib, with a median follow-up of 67 months. 4

Information on ibrutinib

Ibrutinib is a first class Bruton tyrosine kinase inhibitor (BTK) that acts by forming a strong covalent bond with BTK to block the transmission of cell survival signals into malignant B cells. 7 By blocking this BTK protein, ibrutinib contributes to the death and reduction of the number of tumor cells, thus slowing the aggravation of the neoplasm. 8

Currently the use of ibrutinib is approved in Europe for the following indications: 9

chronic lymphocytic leukemia (CLL): as a single agent for the treatment of adult patients with previously untreated CLL, and as a single agent or in combination with bendamustine and rituximab (BR) for the treatment of adult CLL patients who have already undergone at least one previous therapy .
Mantle cell lymphoma (MCL): adult patients with relapsing or refractory MCL forms.
Waldenström macroglobulinemia (WM): patients who have undergone at least one previous therapy or are being treated with first-line therapy in cases where chemo-immunotherapy is not appropriate.
Ibrutinib is approved in over 90 countries and, to date, has been used to treat more than 135,000 patients worldwide and for all approved indications. 10

The most common adverse reactions observed with ibrutinib include diarrhea, neutropenia, haemorrhage (for example: bruising), musculoskeletal pain, nausea, rash and pyrexia. 9

For a full list of side effects and information on dosage and administration, contraindications and other precautions for the use of ibrutinib, please see the Summary of Product Characteristics (SmPC) .

On December 7, 2018 Seattle Genetics, Inc. (Nasdaq: SGEN) and Takeda Pharmaceutical Company Limited (TSE: 4502) reported that ECHELON- step 3 were presented in an oral session 60 in theAnnual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Seattle Genetics, DEC 7, 2018, View Source [SID1234531953]). The data demonstrated that first-line treatment with ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) is effective in prolonging progression-free survival (PFS) and overall survival (OS) with a profile comparable to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), a current standard of treatment in patients with CD30-expressing T-cell peripheral lymphomas (LPCT). These data were also published online in The Lancet. ADCETRIS is an antibody-drug (ADC) conjugate directed to CD30, which is expressed on the surface of various types of LPCT.

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Positive results from the top line of the Phase 3 ECHELON-2 clinical trial were previously reported in October 2018. In November 2018, ADCETRIS was approved by the Food and Drug Administration of the United States (FDA) for adults with systemic anaplastic lymphoma large cells (sALCL) or other LPCT expressing CD30, including angioimmunoblastic T-cell lymphoma and LPCT not specified in combination with CHP. ECHELON-2 data were the basis of a Supplemental Biological Permit (SLB), which was reviewed by the FDA under its Real-Time Oncology Review Pilot Program and approved less than two weeks after the complete submission of supplemental SLB.

"As physicians, we are always on the lookout for new strategies to address unmet needs in aggressive blood cancers and ADCETRIS has proven to be one of those agents with benefit to patients in various types of lymphoma and now in first-line LPCT," said Steven. Horwitz, MD, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center in New York. "This research is important for patients because physicians now have a novel approach to treating newly diagnosed patients with LPCT expressing CD30, a group of aggressive cancers.Data from ECHELON-2 demonstrate that ADCETRIS plus CHP are superior in prolonging progression-free survival and overall survival compared to a current standard of treatment, CHOP, a multi-agent chemotherapy regimen that we have been using in practice for several decades. "

"This is the sixth FDA-approved indication for ADCETRIS in malignant lymphoid tumors and the second as a first-line treatment in combination with chemotherapy," said Roger Dansey, MD, medical director of Seattle Genetics. "Data presented today at ASH (Free ASH Whitepaper) note that the combination of ADCETRIS provides clinically significant benefits for patients with previously untreated LPCT and has the potential to be practice shifting for such patients. "

"We are pleased to share these impressive results from the ECHELON-2 study, which is based on the efficacy and safety observed with ADCETRIS in various CD30-positive lymphomas," said Jesús Gómez-Navarro, MD, vice president and research director and Takeda Clinical Development in Oncology. "The study demonstrated clinically significant results and was the first randomized first-line LPCT Phase 3 trial to show improvement in overall survival. Establishing an optimal therapy for LPCT has been a challenge for clinicians and these findings represent progress in meeting the unmet needs of people living with this serious illness.We look forward to working with regulatory authorities in our territory to bring a possible new treatment option to patients with LPCT. "

The ECHELON-2 trial: Results of a randomized, double-blind, active-controlled phase III study of brentuximab vedotin and CHP (A + CHP) versus CHOP in first-line treatment of patients with peripheral CD30 + T cell lymphomas ( abstract # 997, oral presentation on December 3, 2018 at 6:15 pm at the San Diego Convention Center, Room 6F)

ECHELON-2 is a multicenter, double-blind, randomized, global study evaluating ADCETRIS as part of a first-line chemotherapy regimen in patients with previously untreated LPCT who express CD30. The primary endpoint is SLP by Independent Central Blind Review (BICR), with events defined as progression, death, or chemotherapy for residual or progressive disease. Major secondary endpoints include SLP in patients with sALCL, complete remission rate (RC), SG, and objective response rate (ORT). ECHELON-2 recruited 452 patients (226 in each segment) at 132 sites in 17 countries in North America, Europe, Asia-Pacific and the Middle East. The mean age of the patients was 58 years.

The main conclusions, which will be presented by Dr. Steven Horwitz and published in The Lancet , include:

The ECHELON-2 study reached its primary endpoint with ADCETRIS plus CHP demonstrating a statistically significant improvement in PFS, as assessed by a BICR (hazard ratio [IR] = 0.71, p = 0.0110). This corresponds to a 29% reduction in the risk of progression, death or need for additional antineoplastic therapy for residual or progressive disease.
After an average follow-up time of 36.2 months, the median PFS in ADCETRIS plus CHP control was 48.2 months (95% CI, 35.2% non-assessable) compared to 20.8 months (95% CI, , 12.7-47.6) in the control segment according to the BICR evaluation. The three-year SLP was 57.1% for ADCETRIS plus CHP compared to 44.4% in the control segment.
According to the investigator’s evaluation, ADCETRIS plus CHP demonstrated a statistically significant improvement in PFS (RI = 0.70, p value = 0.0096).
SG in the ADCETRIS plus CHP segment was statistically significant compared to CHOP (RI = 0.66, p = 0.0244). This corresponds to a 34% reduction in the risk of death.
After an average follow-up of 42.1 months, the median OS was not reached for any of the study segments. The SG estimated at three years was 76.8% for ADCETRIS plus CHP, compared to 69.1% for CHOP.
All other important secondary endpoints, including rate of CR and TRO, in addition to SLP in patients with sALCL, were statistically significant in favor of the ADCETRIS plus CHP segment. According to the BICR, the CR rate (68% versus 56%, respectively) and ORT (83% versus 72%, respectively) for the ADCETRIS plus CHP segment were significantly higher than those treated with CHOP (p = 0 value , Î »max and value of p = 0.0032, respectively). According to the investigator’s evaluation, the rate of CR and ORT showed a similar benefit for the ADCETRIS segment plus CHP versus CHOP (p value = 0.0043 and p value = 0.0018, respectively).
Excluding consolidated stem cell transplantation or radiotherapy to consolidate response to initial therapy, 74% of patients in the ADCETRIS plus CHP segment versus 58% of CHOP patients did not require subsequent anti-neoplastic therapies for residual or progressive disease. Of the 226 patients who received CHOP, 49 (22%) received subsequent treatment with a therapy containing ADCETRIS.
The safety profile of ADCETRIS plus CHP in the ECHELON-2 trial was comparable to that of CHOP and consistent with the established safety profile of ADCETRIS in combination with chemotherapy.
Os eventos adversos relacionados com o tratamento mais comuns de qualquer grau que ocorreram em 20% ou mais dos pacientes no segmento ADCETRIS mais CHP e CHOP foram: náusea (46 e 38%, respectivamente), neuropatia sensitiva periférica (45 e 41%, respectivamente), neutropenia (38% cada), diarreia (38 e 20%, respectivamente), obstipação (29 e 30%, respectivamente), alopecia (26 e 25%, respectivamente), pirexia (26 e 19%, respectivamente), vômitos (26 e 17%, respectivamente), fadiga (24 e 20%, respectivamente) e anemia (21 e 16%, respectivamente).
The most common adverse events of Grade 3 or higher that occurred in the ADCETRIS plus CHP and CHOP segments were: neutropenia (35 and 34%, respectively) and anemia (13 and 10%, respectively).
The incidence and severity of neutropenia were similar between study segments and lower in the subgroup of patients receiving primary prophylaxis with granulocyte colony stimulating factor. Febrile neutropenia was reported in 41 patients (18%) in the ADCETRIS plus CHP segment and 33 patients (15%) in the CHOP segment.
Treatment of patients with peripheral neuropathy was observed in 117 patients (52%) in the ADCETRIS plus CHP segment and 124 patients (55%) in the CHOP segment, with a majority of patients with a maximum severity of Grade 1 (64% and 71%, respectively). In the latter follow-up, peripheral neuropathy returned to the baseline or decreased by 50% in ADCETRIS plus CHP patients versus 64% in the CHOP segment, and the mean resolution time was 17 weeks and 11.4 weeks, respectively.
Adverse events leading to death occurred in seven patients (3%) in the ADCETRIS plus CHP segment and nine patients (4%) in the CHOP segment.
See the Important Safety Information, including the Warning in the box, at the end of this press release.

About T-cell lymphomas

Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two main categories of lymphoma: Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. There are over 60 non-Hodgkin lymphoma subtypes that are broadly divided into two major groups: B-cell lymphomas, which develop from abnormal B lymphocytes; and T-cell lymphomas, which develop from abnormal T lymphocytes. There are many different forms of T-cell lymphomas, some of which are extremely rare. T cell lymphomas can be aggressive (fast growing) or indolent (slow growing).

About ADCETRIS (brentuximab vedotin)

ADCETRIS is being tested in more than 70 ongoing clinical trials for CD30-expressing lymphomas. These include the completed Phase 3 ECHELON-2 assay on first-line peripheral T-cell lymphomas (also known as mature T-cell lymphoma), the completed Phase 3 ECHELON-1 assay on untreated Hodgkin’s lymphoma and the ALCANZA assay stage of T-cell lymphoma.

ADCETRIS is an ADC comprising an anti-CD30 monoclonal antibody linked by a protease cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), using proprietary technology from Seattle Genetics. The ADC employs a binding system that is designed to be stable in the bloodstream, but to release MMAE after internalization into CD30-expressing tumor cells.

Injection of ADCETRIS for intravenous infusion has received FDA approval for six indications in adult patients with: (1) previously untreated systemic anaplastic large cell lymphoma (sALCL) or other peripheral CD30-expressing T-cell lymphomas (LPCT), including angioimmunoblastic T cells and unspecified LPCT, in combination with cyclophosphamide, doxorubicin and prednisone, (2) non-previously treated classic III or IV Hodgkin’s lymphoma (LHc) (III) in combination with doxorubicin, vinblastine and dacarbazine; (3) LHc with high risk of relapse or progression such as post-autologous stem cell transplantation (ASCT) consolidation,

Health Canada granted approval of ADCETRIS with conditions for relapsed or refractory Hodgkin’s lymphoma and sALCL in 2013, and unconditional approval for post-autologous stem cell transplantation (ASCT) consolidation treatment of patients with Hodgkin’s lymphoma at risk increased relapse or progression.

ADCETRIS received a conditional marketing authorization from the European Commission in October 2012. The indications approved in Europe are: (1) for the treatment of adult patients with relapsed or refractory Hodgkin’s lymphoma after ASCT or after at least two therapies when treating ASCT or multi-agent chemotherapy is not a treatment option, (2) treatment of adult patients with recurrent or refractory slam, (3) for the treatment of adult patients with CD30 positive Hodgkin’s lymphoma at increased risk of relapse or progression after ASCT, and (4) for the treatment of adult patients with cutaneous CD30-positive T-cell lymphoma (CTCL) after at least one prior systemic therapy.

ADCETRIS has received marketing authorization from regulatory authorities in 72 countries for relapsed or refractory Hodgkin’s lymphoma and sALCL. Please refer to the important safety information, including the Warning in the box, below.

Seattle Genetics and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seattle Genetics has marketing rights in the US and Canada, and Takeda has the right to market ADCETRIS in the rest of the world. Seattle Genetics and Takeda are funding joint development costs for ADCETRIS on a half-way basis, except in Japan, where Takeda is solely responsible for development costs.

On December 7, 2018 Celgene Corporation (NASDAQ: CELG) reported results from the Phase 3 AUGMENT study, showing that REVLIMID (lenalidomide) in combination with rituximab (R 2 ) has resulted in a progression-free survival (PFS) higher in patients with relapsing / refractory indolent lymphoma than patients treated with rituximab plus placebo (R-placebo) (Press release, Celgene, DEC 7, 2018, View Source [SID1234531952]). The data were presented by John Leonard during an oral presentation at the 60th annual meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), which took place in San Diego, California.

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The international randomized, double-blind phase 3 clinical study evaluated the efficacy and safety of the experimental combination of R 2 compared to rituximab plus placebo in patients (n = 358) with follicular lymphoma (n = 295) and lymphoma of the area marginal (n = 63) recurrent / refractory. In the study, the R 2 arm demonstrated a statistically significant improvement in the primary progression-free survival endpoint (PFS), assessed by an independent review board, compared to the R-placebo arm. Mean PFS was 39.4 months for patients treated with R 2 versus 14.1 months for patients treated with R-placebo (P <0.0001; HR: 0.46; 95% CI, 0.34-0.62).

«Data from the AUGMENT study, with R 2 more than doubling progression-free survival compared to rituximab monotherapy, represents a possible new and important treatment option for patients with follicular lymphoma or the relapsing / refractory marginal zone» , said John Leonard , researcher responsible for the AUGMENT study, The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology and Director of the Joint Clinical Trials Office at Weill Cornell Medicine, who also served as a consultant for Celgene.

Overall survival (OS), a secondary endpoint, showed a positive trend in terms of improvement in the R 2 arm compared to the control arm (lethal events: 16 vs 26) (HR: 0.61; 95% CI, 0, 33 to 1.13). The two-year OS rate was 93% for patients treated with R 2 and 87% for patients treated with R-placebo.

The overall response rate (ORR), another secondary endpoint, was 78% (n = 138) in the R 2 arm compared to 53% (n = 96) of the R-placebo arm, according to the independent review committee. The duration of the response (DoR) was significantly increased for R 2 compared to R-placebo with medial DoR of 37 vs 22 months respectively (P = 0.0015; HR: 0.53; 95% CI, 0.36-0 , 79).

The most frequent adverse event (AE) in the R 2 arm was neutropenia (58%), vs. 22% in the R-placebo arm. Other AEs commonly seen in more than 20% of patients included diarrhea (31% in the R 2 arm vs. 23% in the R-placebo arm), constipation (26% vs. 14%, respectively), cough (23% vs. 17% ) and fatigue (22% vs. 18%). Adverse events most commonly reported (> 10%) in the R arm 2 were neutropenia, constipation, leukopenia, anemia, thrombocytopenia and acute exacerbation of symptoms tumor ( tumor flare reaction) . During the AUGMENT study no unexpected results were observed in terms of safety.

"These data represent a new, potential treatment strategy for patients with relapsing / relapsing indolent non-Hodgkin’s lymphomas , " said Celgene’s president of Global Clinical Development, Alise Reicin . "We are anticipating the submission of authorization applications for the first quarter of 2019. to allow patients to access this important combination as soon as possible . "

The use of REVLIMID , alone or in combination with other agents, is currently not approved in any country in the treatment of follicular lymphoma or in that of marginal zone lymphoma.

Information on REVLIMID

REVLIMID (lenalidomide) in combination with dexamethasone (des) is indicated for the treatment of patients with multiple myeloma (MM).

REVLIMID is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT).

REVLIMID is indicated in the treatment of patients with transfusion-dependent anemia due to myelodysplastic syndromes (MDS) at low or intermediate risk 1, associated with a cytogenetic abnormality with 5q deletion, with or without further cytogenetic abnormalities.

REVLIMID is indicated for the treatment of patients with recurrent mantle cell lymphoma (MCL) or with progression of the disease after 2 previous therapies, one of which includes bortezomib.

REVLIMID is not recommended or recommended for the treatment of patients with chronic lymphatic leukemia (LLC) outside of controlled clinical trials.

On December 7, 2018 DiaMedica Therapeutics Inc. ("DiaMedica") (NASDAQ:DMAC) (TSX‑V:DMA), a clinical stage biopharmaceutical company, reported the pricing of its initial public offering in the United States of 4,100,000 of its common shares at a price to the public of $4.00 per share (Press release, DiaMedica, DEC 7, 2018, View Source [SID1234531951]). All of the common shares are being offered by DiaMedica. The common shares are expected to begin trading December 7, 2018 on The Nasdaq Capital Market under the symbol "DMAC." The offering is expected to close on December 11, 2018, subject to the satisfaction of customary closing conditions.

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DiaMedica expects to use the net proceeds from the offering to fund clinical development of DiaMedica’s lead drug candidate, DM199, to conduct research activities and for working capital and general corporate purposes. Craig-Hallum Capital Group LLC is acting as the sole managing underwriter for the initial public offering.

A registration statement relating to these securities has been filed with and was declared effective by the U.S. Securities and Exchange Commission on December 6, 2018. This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.

The offering is being made only by means of a prospectus. A copy of the final prospectus related to the offering may be obtained, when available, from Craig-Hallum Capital Group LLC at 222 South Ninth Street, Suite 350, Minneapolis, Minnesota 55402, Attention: Equity Capital Markets, by telephone at 612-334-6300, or by e-mail at [email protected].

On December 7, 2018 Affimed N.V. (Nasdaq: AFMD), a clinical stage biopharmaceutical company committed to improving patient outcomes through the power of the innate immune system, reported its registrational pathway, updated clinical development plans and the estimated market opportunity for the Company’s lead candidate AFM13 – a first-in-class innate cell engager – at its Research & Development Day in New York City (Press release, Affimed, DEC 7, 2018, View Source [SID1234531950]).

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Affimed plans to initiate a Phase 2 study evaluating the safety and efficacy of AFM13 as monotherapy in relapsed or refractory peripheral T cell lymphoma (PTCL) and transformed mycosis fungoides (TMF), a subset of cutaneous T cell lymphoma (CTCL) in the first half of 2019. Based on preliminary feedback from the U.S. Food and Drug Administration (FDA) and on data presented at this week’s America Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, Affimed believes that results from an open-label, single-arm Phase 2 study could form the basis for a Biologics License Application (BLA) submission and support an accelerated approval, given the unmet medical need for safe and effective new treatments in this hard-to-treat population.

"We believe that the clinical development plan shared today for AFM13 provides potential for accelerated approval and helps to lay the groundwork for further investigations of CD16A innate immune engagers," said Dr. Adi Hoess, Affimed’s CEO. "Through our fit-for-purpose ROCK platform, we continue to generate novel engagers, like AFM13, to broaden our leadership in innate immunity. We look forward to continuing this important work to enhance current immuno-oncology approaches, with the ultimate goal of giving patients back the body’s innate ability to fight cancer."

The broader clinical development strategy for AFM13 includes expanding into other CD30-positive lymphoma indications and additional treatment lines with significant unmet need. In collaboration with strategic partners, Affimed plans to investigate AFM13 in combination with other immunotherapy agents, such as an anti-PD-1/PD-L1 antibody agent and with adoptive NK cell transfer.

"AFM13’s clinical profile to date is very encouraging," said Dr. Leila Alland, Chief Medical Officer of Affimed. "The recently presented data at ASH (Free ASH Whitepaper) increase our confidence that AFM13 holds significant therapeutic value for patients with CD30-positive lymphoma. Our team is looking forward to initiating the registrational study for AFM13 in the first half of 2019 and it is our commitment to develop this potential treatment for patients as quickly as possible."

"Our market research suggests a sizable near-term commercial opportunity for AFM13 with an estimated initial eligible population of about 2,500 patients per year with relapsed or refractory PTCL in the U.S.," said Denise Mueller, Head of Commercial Strategy and Business Development of Affimed. "We believe our clinical development plan for AFM13 combination therapies will further expand the market potential of AFM13 in CD30-positive lymphoma indications such as Hodgkin lymphoma and T cell lymphoma."

Additional Research & Development Day Program Highlights

Dr. Steven M. Horwitz, Associate Attending, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, presented on the current treatment landscape and unmet needs in patients with peripheral and cutaneous T cell lymphomas and Hodgkin lymphoma.

Dr. Ahmed Sawas, Assistant Professor of Medicine, Columbia University College of Physicians and Surgeons and the New York-Presbyterian Hospital, Principal Investigator of the investigator-sponsored Phase 1b/2a trial of AFM13 in CD30-positive lymphoma with cutaneous manifestation led by Columbia University Medical Center, discussed data from the study recently presented at the ASH (Free ASH Whitepaper) Annual Meeting.

Affimed reviewed the updated data from the Phase 1b study of AFM13 as a combination therapy with Merck’s anti-PD-1 antibody Keytruda (pembrolizumab) in relapsed or refractory Hodgkin lymphoma (HL) patients that was presented at the ASH (Free ASH Whitepaper) Annual Meeting.

Dr. Yago Nieto, Professor of Medicine, Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, discussed data from the preclinical research of cord blood derived natural killer cells loaded with AFM13 as off-the-shelf cell therapy for CD30-positive malignancies conducted under Affimed’s sponsored research collaboration with MD Anderson. He concluded that the encouraging data observed in this study, which was featured in an oral presentation at the ASH (Free ASH Whitepaper) Annual Meeting, provide a strong rationale for clinically investigating the strategy of an off-the-shelf adoptive immunotherapy with AFM13-loaded CB-NK cells in patients with relapsed/refractory CD30+ malignancies. Dr. Nieto outlined plans to conduct a clinical study in patients with CD30-positive lymphoma.

Webcast Information

The archived webcast and slides of the presentation are available under the "News & Events" section of Affimed’s website at View Source and will be available for 30 days following the event.

About AFM13
AFM13 is a first-in-class tetravalent, bispecific NK cell engager that specifically binds to CD30 on tumor cells and to CD16A on NK cells. AFM13 is being developed in Hodgkin lymphoma (HL) and in other CD30-positive lymphomas. AFM13 has shown a favorable safety profile and signs of therapeutic efficacy in a monotherapy setting in studies in HL and CD30-positive lymphoma with cutaneous manifestation. In addition, data from a combination study of AFM13 with Merck’s anti-PD-1 antibody Keytruda (pembrolizumab) supports proof of principle for the combination of NK cell engagement with checkpoint inhibition. AFM13 has been granted orphan drug designation by the U.S. Food and Drug Administration.

About Affimed’s ROCK Platform
Affimed’s proprietary, versatile and modular ROCK (Redirected Optimized Cell Killing) platform enables the generation of first-in-class, tetravalent, multi-specific immune cell engagers. Based on its modularity, ROCK allows for antibody engineering of highly customizable innate immune cell and T cell engagers to generate clinical candidates tailored to multiple disease indications and settings, including generation of molecules against validated oncology targets to address the limitations of existing treatments of hematologic and solid tumors.