On December 12, 2021 Wugen, Inc., a clinical-stage biotechnology company developing a pipeline of off-the-shelf cell therapies to treat a broad range of hematological and solid tumor malignancies, reported that new preclinical data supporting the safety and efficacy profile of WU-CART-007 for T-cell malignancies (Press release, Wugen, DEC 12, 2021, View Source [SID1234596862]). Further, today’s data highlighted Wugen’s clinical readiness and robust manufacturing process for WU-CART-007. The U.S. Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for WU-CART-007 and Wugen is preparing for enrollment of a Phase 1/2 clinical trial for relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (LBL) (NCT#04984356).

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WU-CART-007 is an off-the-shelf, fratricide-resistant CD7-targeted CAR-T cell therapy designed to overcome the technological challenges of harnessing CAR-T cells to treat CD7+ hematological malignancies. Wugen is deploying CRISPR/Cas9 gene editing technology to delete CD7 and the T-cell receptor alpha constant (TRAC), preventing CAR-T cell fratricide and mitigating the risk of graft-versus-host-disease (GvHD). WU-CART-007 is manufactured using healthy donor-derived T-cells to eliminate the risk of malignant cell contamination historically observed in the autologous CAR-T setting.

"Adult and pediatric patients with T-cell malignancies experience high rates of relapse and mortality," said Dan Kemp, Ph.D., President and Chief Executive Officer of Wugen. "We believe WU-CART-007 is the first off-the-shelf allogeneic CAR-T cell therapy targeting this category of hematological cancers to receive an IND clearance from the FDA, and our program has tremendous potential to address this critical unmet need for patients. Today’s preclinical data validate our approach and support the clinical advancement of WU-CART-007. We look forward to enrolling patients in our Phase 1/2 clinical trial to evaluate WU-CART-007 in R/R T-ALL and LBL."

Key findings reported in the poster include:

Wugen has developed a robust manufacturing process to enable clinical development of WU-CART-007, using healthy donor-derived T-cells to eliminate the risk of malignant cell contamination, and CRISPR/Cas9 gene editing to prevent fratricide and mitigate the risk of GvHD.
WU-CART-007 models primarily a T-cell central memory phenotype with enhanced functionality.
WU-CART-007 exhibits strong CD7-specific anti-tumor activity in vitro and in vivo, with a favorable off-target profile.
Robust pre-clinical data support clinical development of WU-CART-007 in CD7+ hematological malignancies. A Phase 1/2 clinical trial evaluating WU-CART-007 in patients with R/R T-ALL/LBL will open for enrollment in December 2021.

On December 12, 2021 Epizyme, Inc. (Nasdaq: EPZM), a fully integrated, commercial-stage biopharmaceutical company developing and delivering transformative therapies against novel epigenetic targets, reported that updated safety and activity data from the Phase 1b portion of its Phase 1b/3 confirmatory study evaluating the investigational use of TAZVERIK (tazemetostat), a first-in-class, oral, selective inhibitor of EZH2, in combination with rituximab + lenalidomide (R2) in patients with relapsed/refractory follicular lymphoma (FL) who have been treated with at least one prior systemic therapy, including patients who are rituximab-refractory and/or POD24, at the 2021 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, Epizyme, DEC 12, 2021, View Source [SID1234596859]).

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Updated data from the Phase 1b portion of the study reported today included 40 FL patients who had received treatment with tazemetostat and R2 (400 mg [n=4], 600 mg [n=18], or 800 mg [n=18]) as of the September 29, 2021 data cut-off. The findings demonstrated that the safety profile of the tazemetostat and R2 combination was consistent with the previously reported safety information in the prescribing information for both tazemetostat and R2, respectively. Additionally, there was no clear dose response for treatment-emergent adverse events (TEAEs) or dose modifications. Thirty-five of the 40 patients were evaluable for tumor assessments as of the data cut off, with 32 patients responding to treatment. The activity findings showed an objective response rate of 91.4 percent (37.1 percent complete response rate and 54.3 percent partial response rate). The duration of response data continue to mature as the study is ongoing.

"The data presented today on the combination of rituximab, lenalidomide and tazemetostat, known as R2 + tazemetostat, have shown promising responses in the second-line FL setting and the side effects observed to date have been consistent with lenalidomide-based combinations," said Connie Lee Batlevi, MD PhD, medical oncologist with Memorial Sloan Kettering Cancer Center. "We are excited to start the randomized Phase 3 portion of the study, with the hope of developing a chemotherapy-free combination regimen for patients with follicular lymphoma."

SYMPHONY-1 (EZH-302) is an international, multicenter, randomized, double-blind, active-controlled, 3-stage, biomarker-enriched, confirmatory Phase 1b/3 study, which is designed to evaluate the safety and efficacy of tazemetostat in combination with R2 in patients with relapsed or refractory FL after at least one prior line of therapy. The Phase 1b portion of the study is designed to determine the recommended Phase 3 dose, activity, and safety of tazemetostat and R2. In addition to the safety run-in analysis, the study also assessed the pharmacokinetics and continues to assess clinical activity of tazemetostat when administered in combination with R2.

The Phase 1b safety run-in component evaluated tazemetostat at three dose levels (400 mg, 600 mg, and 800 mg orally twice daily) in 28-day cycles with standard-dose R2 using a 3 + 3 design. Rituximab was administered at 375 mg/m2 intravenously on days 1, 8, 15 and 22 of cycle 1, then on day 1 of cycles 2 to 5. Lenalidomide was administered at 20 mg (creatinine clearance ≥60 mL/min) or 10 mg (if creatinine clearance <60 mL/min) orally once daily on days 1 to 21 every 28 days for 12 cycles. In the Phase 3 component, approximately 500 patients will be randomly assigned to receive the RP3D of tazemetostat + R2 or placebo + R2. The study will also include a maintenance arm with tazemetostat or placebo following the first year of treatment with tazemetostat + R2 or placebo + R2.

Treatment with tazemetostat and R2 was generally well tolerated. Grade 3/4 TEAEs were observed in 17 (42.5%) patients; the most common grade 3/4 TEAE (≥10%) was neutrophil count decrease/neutropenia (15.0.%) Ten patients (25.0%) reported a total of 16 SAEs (serious adverse events). The only SAE reported in >1 patient was COVID-19, reported in 2 patients; all other SAEs were reported in 1 patient each.

A table of the activity findings as of the data cut off are below:

Best Overall Response (BOR) Ratea, n (%)

Tazemetostat + R2 (n = 35)

Objective Response Rate (ORR)

32 (91.4)

Complete Responseb (CR)

13 (37.1)

Partial Response (PR)

19 (54.3)

Stable Disease (SD)

3 (8.6)

Progressive Disease (PD)

0

a For BOR, there were 27 PET-CT-based responses and 8 CT-based responses.

b For CR, 12 were PET-CT-based responses and 1 was a CT-based response.

"We are encouraged to share progress of our tazemetostat program in follicular lymphoma with the cancer community, as we believe these data support the potential tazemetostat may play as a backbone of therapy in combination with current standards of care for patients living with the disease. We will continue to monitor these patients and we look forward to sharing follow-up data as they mature over time," said Dr. Shefali Agarwal, Executive Vice President and Chief Medical and Development Officer at Epizyme. "At Epizyme, we are committed to advancing the follicular lymphoma treatment landscape for patients, the healthcare teams who treat them, and the families who support them."

In addition to the SYMPHONY-1 presentation (Abstract #2207), two additional tazemetostat studies are being presented during the ASH (Free ASH Whitepaper) Annual Meeting. The first is a trial-in-progress/study design presentation for SYMPHONY-2 (Abstract #3541), a multi-center, open-label, single-arm, Phase 2 study of tazemetostat in combination with rituximab for the treatment of relapsed or refractory FL. The trial is actively enrolling patients across 18 sites in the United States. The second presentation (Abstract #1183) focuses on the analysis of the molecular and genetic characterization of patients treated with tazemetostat to better understand the drivers of response to treatment.

About TAZVERIK (tazemetostat)

TAZVERIK is a methyltransferase inhibitor indicated for the treatment of:

Adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
Adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an EZH2 mutation as detected by an FDA-approved test and who have received at least two prior systemic therapies.
Adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.
These indications are approved under accelerated approval based on overall response rate and duration of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.

The most common (≥20%) adverse reactions in patients with epithelioid sarcoma are pain, fatigue, nausea, decreased appetite, vomiting and constipation. The most common (≥20%) adverse reactions in patients with follicular lymphoma are fatigue, upper respiratory tract infection, musculoskeletal pain, nausea and abdominal pain.

View the U.S. Full Prescribing Information here: Epizyme.com

On December 12, 2021 Xencor, Inc. (NASDAQ:XNCR), a clinical-stage biopharmaceutical company developing engineered monoclonal antibodies and cytokines for the treatment of cancer and autoimmune diseases, reported updated data from its Phase 1 dose-escalation study of plamotamab, a CD20 x CD3 bispecific antibody, in patients with B-cell non-Hodgkin lymphomas (Press release, Xencor, DEC 12, 2021, View Source [SID1234596832]). Data will be presented by Krish Patel, M.D., Director of the Lymphoma Program at Swedish Cancer Institute, in a poster session today from 6:00 p.m. to 8:00 p.m. EST at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Atlanta, Georgia.

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"Plamotamab is generally well tolerated and demonstrates encouraging clinical activity in heavily pretreated patients at our recommended intravenous Phase 2 dose of 50 mg flat dosing every two weeks following step-up dosing. Additionally, our pharmacokinetic modeling supports subcutaneous administration, which we plan to incorporate next year into our ongoing Phase 1 monotherapy study," said Allen Yang, M.D., Ph.D., senior vice president and chief medical officer at Xencor. "We are especially encouraged that these results support the potential for a differentiated safety profile and better outcomes for patients when plamotamab is combined with other agents in a chemotherapy-free regimen. To that end, early next year we will initiate the first combination study, with tafasitamab and lenalidomide, in patients with relapsed or refractory diffuse large B cell lymphoma. Additionally, our new worldwide collaboration with Janssen for advancing plamotamab development expands our strategy to develop multiple highly active chemotherapy-free regimens across B-cell cancers, importantly with tumor-selective, co-stimulatory CD28 bispecific antibodies."

Study Design

The Phase 1 study of plamotamab was originally designed in two parts: Part A to establish an initial priming dose with fixed, weight-based dosing regimens and Part B to escalate dosing on administrations after the priming dose (doses between 80 and 360 mcg/kg). A third part, Part C, was added to establish a step-up dosing regimen with higher, flat and less frequent dosing.

The Part C schedule, an intravenous, 50 mg flat dose every two weeks after step-up dosing during the first two cycles of treatment, was generally well tolerated and was determined to be the recommended Phase 2 dose.

Expansion cohorts are actively recruiting patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) and are dosing using the recommended Phase 2 regimen to further evaluate the safety and efficacy of plamotamab monotherapy.

Safety Analysis

The safety population included 50 patients in Part B (38 DLBCL, 12 FL) and 14 patients in Part C (8 DLBCL, 4 FL, 1 marginal zone lymphoma, 1 mantle cell lymphoma). Patients were heavily pretreated, had a median age of 61.5 years, had a median of 4 prior therapies and had been diagnosed a median of 26.5 months prior to treatment.

In Part C of the study, patients had generally more advanced disease and poorer responses to prior therapy. The Part C population had a median age of 64 years, had a median of 5 prior therapies and had been diagnosed a median of 30.5 months prior to treatment. Of the 14 patients in Part C, eight patients received prior CAR-T and three patients received NK cell therapy. Two of these patients received both. All eight patients with DLBCL received prior CAR-T therapy.

The most common Grade 3 or 4 treatment-emergent adverse events (AEs) across all patients were anemia (21%), neutropenia (19%), hypophosphatemia (11%), thrombocytopenia (11%) and lymphopenia (10%). Four patients (5%) experienced Grade 3 or 4 cytokine release syndrome (CRS), each instance on the first dose, and no patients experienced Grade 3 or 4 CRS in Part C of the study. The rate of CRS of any grade fell from 74% in Part B to 57% in Part C. CRS was generally manageable with premedication.

In Part C, safety events were generally mild or moderate in severity. Grade 3 or 4 AEs experienced by more than 5% of patients included anemia (14%), lymphopenia (14%) and one patient each (7%) experiencing neutropenia, thrombocytopenia, decreases in neutrophil count, transaminase increases, fatigue and gamma-glutamyl transferase increases. Nervous system events did not lead to discontinuations, and no related neurotoxicity greater than Grade 2 was observed.

Efficacy Analysis

The efficacy analysis included 47 evaluable patients with either DLBCL or FL who were treated in Part B (n=38) or in Part C (n=9). Responses were assessed based on the Lugano Classification. The objective response rate (ORR) was 51% (24/47), and complete responses (CR) were observed in 12 patients (26%).

In part C of the study, the ORR was 100% (4/4) for patients with follicular lymphoma (FL), and CRs were observed in two patients (50%). For patients with diffuse large B-cell lymphoma, the ORR was 40% (2/5), and a CR was observed in one patient (20%). All 5 evaluable patients with DLBCL received prior CAR-T therapy, and two evaluable patients with DLBCL received prior NK cell therapy.

At the data cut off, the median duration of response for weight-based dosing cohorts and Part C was 225 days for patients with DLBCL and 171 days for patients with FL, with six patients continuing to respond to plamotamab monotherapy.

The poster will be archived under "Events & Presentations" in the Investors section of the Company’s website located at www.xencor.com.

About Plamotamab

Plamotamab is an investigational tumor-targeted XmAb bispecific antibody that contains both a CD20 binding domain and a cytotoxic T-cell binding domain (CD3). CD20 is highly expressed across a range of B-cell tumors, including non-Hodgkin lymphoma (NHL). Engagement of CD3 by plamotamab activates T cells for highly potent and targeted killing of CD20-expressing tumor cells.

Plamotamab is currently being evaluated in a Phase 1 clinical study for the treatment of patients with CD20-expressing hematologic malignancies, including NHL. Preliminary safety and anti-tumor activity from the Phase 1 study indicates that plamotamab is generally well tolerated and demonstrates encouraging clinical activity as a monotherapy.

Xencor has entered an exclusive collaboration and worldwide license agreement with Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, to develop and commercialize plamotamab and novel XmAb B-cell targeting bispecific antibodies that are designed to conditionally activate T cells through the CD28 co-stimulatory receptor.

On December 12, 2021 Seagen Inc. (Nasdaq:SGEN) reported promising efficacy and safety results from Part B of an open-label, phase 2 clinical trial evaluating ADCETRIS (brentuximab vedotin) in a novel combination with nivolumab, doxorubicin, and dacarbazine (AN+AD) as a frontline treatment for patients with advanced stage classical Hodgkin lymphoma (cHL) (Press release, Seagen, DEC 12, 2021, View Source [SID1234596831]). Data from this preliminary analysis were presented (Abstract #2454) as part of a poster presentation at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in Atlanta.

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The preliminary results demonstrated a complete response rate of 88 percent (95% CI: 75.9, 94.8) and overall response rate of 93 percent (95% CI: 82.7, 98.0) among 56 patients who had an end of treatment assessment on or prior to the data cutoff date. Patients received up to six cycles of treatment and were evaluated after two cycles of therapy and at the end of treatment. AN+AD was well-tolerated and no new safety signals were observed.

"I am excited about this combination of brentuximab vedotin and nivolumab along with a simplified chemotherapy regimen for the frontline treatment of patients with advanced stage classical Hodgkin lymphoma," said Hun Ju Lee, M.D., Associate Professor of Medicine, Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston. "This combination demonstrated a low incidence of peripheral neuropathy and the absence of febrile neutropenia. What we are learning from our research is that the use of two active targeted agents with distinct and complementary mechanisms of action in the first-line setting shows promising activity and a tolerable safety profile."

"We are optimistic about novel combination approaches to improve outcomes in patients following a diagnosis of classical Hodgkin lymphoma, and we are encouraged by these data evaluating ADCETRIS plus nivolumab, doxorubicin and dacarbazine as a first-line therapy," said Roger Dansey, M.D., Chief Medical Officer at Seagen. "We look forward to complete results from this trial and adding to the breadth of evidence for ADCETRIS in the treatment of advanced classical Hodgkin lymphoma."

Efficacy:

Among 56 patients who had an end of treatment assessment on or prior to the data cutoff date, there was a complete response rate of 88 percent (95% CI: 75.9, 94.8) and overall response rate of 93 percent (95% CI: 82.7, 98.0).
Safety:

The most frequently reported treatment-related treatment-emergent adverse events (AEs) occurring in more than 20 percent of patients who received AN+AD included nausea (65%), fatigue (46%), peripheral sensory neuropathy (39%), alopecia (35%), diarrhea (30%) and constipation (25%).
Immune-mediated AEs were observed in 18 patients (32%) and eight patients (14%) experienced treatment-related treatment-emergent serious AEs.
Two patients (4%) experienced Grade > 3 peripheral neuropathy and no patients discontinued treatment due to peripheral neuropathy. No febrile neutropenia was observed, and there were no Grade 5 adverse events.
See ADCETRIS U.S. Important Safety Information, including Boxed Warning, below.

About the SGN35-027 Clinical Study

SGN35-027 is an ongoing open-label, multiple part, multicenter, phase 2 clinical trial evaluating two brentuximab vedotin treatment combinations in patients with advanced stage classical Hodgkin lymphoma. The trial includes three parts (Parts A, B, and C). Part A includes a combination of brentuximab vedotin and doxorubicin, vinblastine and dacarbazine (A+AVD), while Parts B and C include brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine (AN+AD). The primary endpoint for Part A is the proportion of patients with treatment-emergent incidence of rate of febrile neutropenia. The primary endpoint for Parts B and C is the proportion of participants with complete response at end of treatment, according to the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). Key secondary endpoints include safety, tolerability, ORR, and PFS. Incidence of adverse events is a secondary endpoint for Parts B and C.

About Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma (cHL), Hodgkin disease, or Hodgkin, is a cancer of the blood. It starts when lymphocytes, a type of white blood cell, grow out of control. People with cHL have abnormal white blood cells called Reed-Sternberg cells in their lymph nodes. These cells usually have a special protein on their surface called CD30, which is a key marker of cHL. CD30 is present in approximately 95 percent of all cases of Hodgkin lymphoma. In 2021, it is estimated that there will be 8,830 new cases of Hodgkin lymphoma and an estimated 960 people will die of this disease in the U.S.1

About ADCETRIS

ADCETRIS is an antibody-drug conjugate (ADC) comprising an anti-CD30 monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing cells.

ADCETRIS is indicated for the treatment of adult patients with:

previously untreated Stage III or IV classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vinblastine, and dacarbazine,
cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation,
cHL after failure of auto-HSCT or failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates,
previously untreated systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone,
sALCL after failure of at least one prior multi-agent chemotherapy regimen, and
primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides who have received prior systemic therapy.
ADCETRIS has received marketing authorization in more than 70 countries for certain types of relapsed or refractory Hodgkin lymphoma and sALCL.

Seagen and Takeda are jointly developing ADCETRIS. Under the terms of the collaboration agreement, Seagen has U.S. and Canadian commercialization rights and Takeda has rights to commercialize ADCETRIS in the rest of the world. Seagen and Takeda are funding joint development costs for ADCETRIS on a 50:50 basis, except in Japan where Takeda is solely responsible for development costs.

ADCETRIS (brentuximab vedotin) for injection U.S. Important Safety Information

BOXED WARNING

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML): JC virus infection resulting in PML and death can occur in ADCETRIS-treated patients.

Contraindication

ADCETRIS concomitant with bleomycin due to pulmonary toxicity (e.g., interstitial infiltration and/or inflammation).

Warnings and Precautions

Peripheral neuropathy (PN): ADCETRIS causes PN that is predominantly sensory. Cases of motor PN have also been reported. ADCETRIS-induced PN is cumulative. Monitor for symptoms such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Institute dose modifications accordingly.
Anaphylaxis and infusion reactions: Infusion-related reactions (IRR), including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an IRR occurs, interrupt the infusion and institute appropriate medical management. If anaphylaxis occurs, immediately and permanently discontinue the infusion and administer appropriate medical therapy. Premedicate patients with a prior IRR before subsequent infusions. Premedication may include acetaminophen, an antihistamine, and a corticosteroid.
Hematologic toxicities: Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (≥1 week) severe neutropenia and Grade 3 or 4 thrombocytopenia or anemia can occur with ADCETRIS.
Administer G-CSF primary prophylaxis beginning with Cycle 1 for patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL.

Monitor complete blood counts prior to each ADCETRIS dose. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent doses.

Serious infections and opportunistic infections: Infections such as pneumonia, bacteremia, and sepsis or septic shock (including fatal outcomes) have been reported in ADCETRIS-treated patients. Closely monitor patients during treatment for bacterial, fungal, or viral infections.
Tumor lysis syndrome: Closely monitor patients with rapidly proliferating tumor and high tumor burden.
Increased toxicity in the presence of severe renal impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with severe renal impairment compared to patients with normal renal function. Avoid use in patients with severe renal impairment.
Increased toxicity in the presence of moderate or severe hepatic impairment: The frequency of ≥Grade 3 adverse reactions and deaths was greater in patients with moderate or severe hepatic impairment compared to patients with normal hepatic function. Avoid use in patients with moderate or severe hepatic impairment.
Hepatotoxicity: Fatal and serious cases have occurred in ADCETRIS-treated patients. Cases were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, and occurred after the first ADCETRIS dose or rechallenge. Preexisting liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Monitor liver enzymes and bilirubin. Patients with new, worsening, or recurrent hepatotoxicity may require a delay, change in dose, or discontinuation of ADCETRIS.
PML: Fatal cases of JC virus infection resulting in PML have been reported in ADCETRIS-treated patients. First onset of symptoms occurred at various times from initiation of ADCETRIS, with some cases occurring within 3 months of initial exposure. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider PML diagnosis in patients with new-onset signs and symptoms of central nervous system abnormalities. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.
Pulmonary toxicity: Fatal and serious events of noninfectious pulmonary toxicity, including pneumonitis, interstitial lung disease, and acute respiratory distress syndrome, have been reported. Monitor patients for signs and symptoms, including cough and dyspnea. In the event of new or worsening pulmonary symptoms, hold ADCETRIS dosing during evaluation and until symptomatic improvement.
Serious dermatologic reactions: Fatal and serious cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with ADCETRIS. If SJS or TEN occurs, discontinue ADCETRIS and administer appropriate medical therapy.
Gastrointestinal (GI) complications: Fatal and serious cases of acute pancreatitis have been reported. Other fatal and serious GI complications include perforation, hemorrhage, erosion, ulcer, intestinal obstruction, enterocolitis, neutropenic colitis, and ileus. Lymphoma with preexisting GI involvement may increase the risk of perforation. In the event of new or worsening GI symptoms, including severe abdominal pain, perform a prompt diagnostic evaluation and treat appropriately.
Hyperglycemia: Serious cases, such as new-onset hyperglycemia, exacerbation of pre-existing diabetes mellitus, and ketoacidosis (including fatal outcomes) have been reported with ADCETRIS. Hyperglycemia occurred more frequently in patients with high body mass index or diabetes. Monitor serum glucose and if hyperglycemia develops, administer anti-hyperglycemic medications as clinically indicated.
Embryo-fetal toxicity: Based on the mechanism of action and animal studies, ADCETRIS can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus, and to avoid pregnancy during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.
Most Common (≥20% in any study) Adverse Reactions

Peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, and mucositis.

Drug Interactions

Concomitant use of strong CYP3A4 inhibitors or inducers has the potential to affect the exposure to monomethyl auristatin E (MMAE).

Use in Specific Populations

Moderate or severe hepatic impairment or severe renal impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for at least 6 months after the final dose of ADCETRIS.

Advise patients to report pregnancy immediately and avoid breastfeeding while receiving ADCETRIS.

On December 12, 2021 AstraZeneca reported that Updated results from the ASCEND Phase III trial showed it’s Calquence (acalabrutinib) maintained a statistically significant progression-free survival (PFS) benefit at three years compared to investigator’s choice of rituximab combined with either idelalisib (IdR) or bendamustine (BR) in adults with relapsed or refractory chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in adults (Press release, AstraZeneca, DEC 12, 2021, View Source [SID1234596830]).1,2

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These data, presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, demonstrated Calquence reduced the risk of disease progression or death by 71% versus IdR/BR as assessed by investigators at three years (based on a hazard ratio [HR] of 0.29; 95% confidence interval [CI]: 0.21-0.41; p<0.0001). Similar clinical benefits were observed in an exploratory analysis comparing each regimen with Calquence. Safety and tolerability of Calquence were consistent with earlier findings, with no new safety signals identified.1

Additional safety analyses from the ELEVATE-RR Phase III trial were also presented at ASH (Free ASH Whitepaper) to further characterise adverse events (AEs) related to treatment with Bruton’s tyrosine kinase (BTK) inhibitors Calquence and ibrutinib. Overall, patients on ibrutinib experienced a 37% higher burden of AEs of any grade versus patients on Calquence.3

For any grade atrial fibrillation/flutter, a key secondary endpoint in the ELEVATE-RR trial, median time to onset was longer for Calquence versus ibrutinib (28.8 versus 16.0 months), and cumulative incidence was lower at all timepoints from six months through two years.3

Additionally, the ELEVATE-RR Phase III trial showed incidence of all-grade atrial fibrillation/flutter was lower for Calquence across subgroups of age, prior line of therapy and among patients without prior history of heart complications.3 Atrial fibrillation is an irregular heart rate that can increase the risk of stroke, heart failure and other heart-related complications.4

John F. Seymour, MBBS PhD, Peter MacCallum Centre and the Royal Melbourne Hospital, and a lead investigator on the ELEVATE-RR trial, said: "Patients with relapsed or refractory chronic lymphocytic leukaemia face limited options to successfully manage their disease, as they are often older and dealing with significant comorbidities. The risk of cardiac adverse events is an important consideration, especially for treatment with Bruton’s tyrosine kinase inhibitors because they can produce significant morbidity in some cases and also lead patients to discontinue treatment. The ELEVATE-RR data provide compelling evidence that acalabrutinib is a more tolerable option with reduced cardiovascular toxicity, giving clinicians further reassurance when prescribing this medicine that fewer patients will need to cease treatment due to adverse events, thus maintaining ongoing control of their disease, even in this complex setting."

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: "These impressive new long-term data support Calquence as the preferred therapy for the most common type of leukaemia in adults, with favourable safety compared to the current standards of care. The totality of the ASCEND and ELEVATE-RR data, in addition to data introducing a new tablet formulation for patients who need alternative methods of taking Calquence, continues to reinforce the positive experience that this medicine can deliver for patients with chronic lymphocytic leukaemia."

Notes

ASCEND: Three-year follow-up data for Calquence in relapsed or refractory CLL (abstract #393)
ASCEND is a global, randomised, multicentre, open-label, Phase III trial that evaluated the efficacy and safety of Calquence (100mg twice-daily until disease progression or unacceptable toxicity) versus investigator’s choice of IdR or BR in patients with relapsed or refractory CLL.1,5 ASCEND is the first randomised trial to directly compare a BTK inhibitor as monotherapy with standard chemoimmunotherapy or idelalisib and rituximab combinations.

AEs led to treatment discontinuation in 21% of patients on Calquence, 65% of patients on IdR and 17% of patients on BR. Events of clinical interest for Calquence versus comparators included atrial fibrillation/flutter (all grade, 6% and 3%, respectively), hypertension (all grade, 7% and 4%), major haemorrhage (all grade, 3% in both arms), infections (Grade ≥3, 25% and 27%, respectively) and second primary malignancies excluding non-melanoma skin cancer (all grade, 7% and 3%, respectively). Serious AEs (any-grade) occurred in 38% of patients treated with Calquence, 63% of IdR patients and 26% of BR patients.1

ELEVATE-RR: Additional safety analyses of Calquence versus ibrutinib in relapsed or refractory CLL (abstract #3721)
Results from the ELEVATE-RR Phase III trial were first presented on 7 June 2021 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and published in the Journal of Clinical Oncology on 26 July 2021.

Additional safety data were used to characterise BTK inhibitor-related AEs, using measures of frequency, duration and drug exposure (versus incidence alone) to measure AE burden. Median treatment exposures were 38.3 months in the Calquence arm and 35.5 months in the ibrutinib arm.3

For any-grade hypertension, median time to onset was similar for Calquence and ibrutinib (8.1 months versus 7.0), but cumulative incidence was lower for Calquence at 6 months (5% versus 12%), 12 months (6% versus 16%), 18 months (8% versus 20%) and 24 months (8% versus 23%).

Hypertension also occurred less frequently with Calquence versus ibrutinib in subgroups of age, prior line of therapy and among patients without prior history.3

Among cardiovascular AEs of clinical interest, incidences of any-grade atrial fibrillation/flutter, hypertension and bleeding were statistically higher with ibrutinib versus Calquence, with higher exposure-adjusted incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exposure-adjusted time with event (2.8-, 3.7-, and 1.8-fold).3

CLL
CLL is the most common type of leukaemia in adults, with an estimated 114,000 new cases globally in 2017, and the number of people living with CLL is expected to grow with improved treatment as patients live longer with the disease.2,6-8

In CLL, too many blood stem cells in the bone marrow become abnormal lymphocytes and these abnormal cells have difficulty fighting infections. As the number of abnormal cells grows, there is less room for healthy white blood cells, red blood cells and platelets. This could result in anaemia, infection and bleeding.6 B-cell receptor signalling through BTK is one of the essential growth pathways for CLL.

ASCEND
ASCEND (ACE-CL-309) is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy of Calquence in patients with relapsed or refractory CLL.5,9

In the trial, 310 patients were randomised (1:1) into two treatment arms. Patients in the first arm received Calquence monotherapy (100mg twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received physician’s choice of either rituximab, a CD20 monoclonal antibody, in combination with idelalisib, a PI3-kinase inhibitor, or rituximab in combination with bendamustine, a chemotherapy.9

The primary endpoint at the interim analysis was PFS assessed by an Independent Review Committee (IRC), and key secondary endpoints included investigator-assessed PFS, IRC- and investigator-assessed overall response rate and duration of response, as well as overall survival, patient-reported outcomes and time to next treatment.

ASCEND is the first randomised Phase III trial to directly compare a BTK inhibitor as monotherapy to these combinations in relapsed or refractory CLL.5,9

ELEVATE-RR
ELEVATE-RR (ACE-CL-006) is a randomised, multicentre, open-label Phase III non-inferiority trial of Calquence versus ibrutinib in patients with relapsed or refractory CLL after at least one prior therapy, and at least one of the following prognostic factors: presence of 17p deletion, or presence of 11q deletion.10,11

In the trial, 533 patients were randomised (1:1) into two arms. Patients in the first arm received Calquence (100mg orally twice-daily until disease progression or unacceptable toxicity). Patients in the second arm received ibrutinib (420mg orally once-daily until disease progression or unacceptable toxicity).11

The primary endpoint for the trial was IRC-assessed PFS (non-inferiority; tested after 250 events, upper margin of 95% CI for HR<1.429). Secondary endpoints included incidence of atrial fibrillation, incidence of Grade 3 or higher infections, incidence of Richter’s transformation (a condition in which CLL changes into an aggressive form of lymphoma12) and OS.11

ELEVATE-RR is the first randomised Phase III trial to directly compare two BTK inhibitors as monotherapy in relapsed or refractory CLL.

Calquence
Calquence (acalabrutinib) is a next-generation, selective inhibitor of BTK. Calquence binds covalently to BTK, thereby inhibiting its activity.13,14 In B cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis and adhesion.13

Calquence is approved for the treatment of CLL and small lymphocytic lymphoma (SLL) in the US, approved for CLL in the EU and several other countries worldwide and approved in Japan for relapsed or refractory CLL and SLL. A Phase I trial is currently underway in Japan for the treatment of front-line CLL.

In the US and several other countries, Calquence is also approved for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The US MCL indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Calquence is not currently approved for the treatment of MCL in Europe or Japan.

As part of an extensive clinical development programme, AstraZeneca and Acerta Pharma are currently evaluating Calquence in more than 20 company-sponsored clinical trials. Calquence is being evaluated for the treatment of multiple B-cell blood cancers including CLL, MCL, diffuse large B-cell lymphoma, Waldenström’s macroglobulinaemia, follicular lymphoma and other haematologic malignancies.

AstraZeneca in haematology
AstraZeneca is pushing the boundaries of science to redefine care in haematology. Applying our deep understanding of blood cancers and leveraging our strength in solid tumour oncology, we are driving the development of novel therapies designed to target underlying drivers of disease across six scientific platforms.

By addressing blood cancers with high unmet medical needs, our aim is to deliver innovative medicines and approaches to healthcare services that have a meaningful impact on patients and caregivers, transforming the haematologic cancer care experience.

AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.