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Seagen Announces U.S. FDA Approval of New Indication for ADCETRIS® (brentuximab vedotin) for Children with Previously Untreated High Risk Hodgkin Lymphoma

Approval Based on Phase 3 Clinical Study That Demonstrated a 59% Reduction in Risk of Disease Progression or Relapse, Second Malignancy or Death vs. Standard of Care

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Seagen Inc. (Nasdaq: SGEN) today announced that the U.S. Food and Drug Administration (FDA) has approved ADCETRIS® (brentuximab vedotin) for the treatment of pediatric patients 2 years and older with previously untreated high risk classical Hodgkin lymphoma (cHL), in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide.

The approval is based on data from a phase 3 study (AHOD1331) conducted by the Children’s Oncology Group (COG) and funded by the National Cancer Institute that showed patients receiving ADCETRIS in combination with standard of care dose-intensive chemotherapy AVE-PC (Adriamycin [doxorubicin], vincristine, etoposide, prednisone and cyclophosphamide) had superior event-free survival (EFS) compared to patients who received standard of care chemotherapy ABVE-PC (Adriamycin [doxorubicin], bleomycin, vincristine, etoposide, prednisone and cyclophosphamide). Patients had a 59% reduction in the risk of disease progression or relapse, second cancer or death (Hazard ratio 0.41 [95% Confidence Interval: 0.25, 0.67]; p=0.0002).

“ADCETRIS is a groundbreaking medicine approved for adults with certain types of lymphomas. Today’s FDA approval extends its availability to younger patients with high-risk classical HL,” said Marjorie Green, M.D., Senior Vice President and Head of Late-Stage Development, Seagen. “We want to acknowledge and thank the patients, families and care providers who participated in the Children’s Oncology Group clinical trial that supported this approval.”

“We are excited about the approval of ADCETRIS for children and adolescents with high risk classical Hodgkin lymphoma because this medicine, which has become part of standard of care for adults with previously untreated advanced stage Hodgkin lymphoma, will now be accessible to young patients as well,” said Sharon M. Castellino, M.D., M.Sc., Professor, Department of Pediatrics, Emory University School of Medicine, AHOD1331 Study Chair and COG Hodgkin Lymphoma Disease Committee Chair.

Hodgkin lymphoma is blood cancer that starts when lymphocytes, a type of white blood cell, grow out of control. It represents about 6% of all childhood cancers and is the most common cancer diagnosed in adolescents ages 15 to 19 years.1,2 About one-third of all Hodgkin lymphoma patients are classified as high risk, typically stage IIB, IIIB, and IVA or IVB.3,4 People with cHL have abnormal white blood cells that usually have a special protein on their surfaces called CD30, a key marker of cHL.

About AHOD1331

AHOD1331 is a National Cancer Institute (NCI)-sponsored study conducted by the Children’s Oncology Group (COG), and is the largest multicenter, randomized, open-label phase 3 immunotherapy study ever conducted with newly diagnosed high risk Hodgkin lymphoma (HL) pediatric patients. The study enrolled 587 patients from 2 to 21 years of age across 151 institutions who had previously untreated HL stages IIB + bulk, IIIB, IVA and IVB. Patients were randomized to five cycles of either standard of care dose-intensive chemotherapy (Adriamycin [doxorubicin], bleomycin. vincristine, etoposide, prednisone and cyclophosphamide [ABVE-PC]) or brentuximab vedotin plus AVE-PC (BV-AVE-PC) given every 21 days with granulocyte colony-stimulating factor support. The primary objective was event-free survival (EFS); events included relapse/progression, second malignant neoplasm (SMN) or death. Seagen provided brentuximab vedotin for the study.

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/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine.
  • Pediatric patients 2 years and older with previously untreated high risk cHL in combination with doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide.
  • Adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation.
  • Adult patients with cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates.
  • Adult patients with 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.
  • Adult patients with sALCL after failure of at least one prior multi-agent chemotherapy regimen.
  • Adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy.

Seagen and Takeda jointly develop 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

Contraindicated with concomitant 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. Patients experiencing new or worsening PN may require a delay, change in dose, or discontinuation of ADCETRIS.

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 adult patients who receive ADCETRIS in combination with chemotherapy for previously untreated Stage III/IV cHL or previously untreated PTCL, and pediatric patients who receive ADCETRIS in combination with chemotherapy for previously untreated high risk cHL.

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 infections.

Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden may be at increased risk. Monitor closely and take appropriate measures.

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. 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. 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 pre-existing 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 this potential risk, and to avoid pregnancy during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.

ADVERSE REACTIONS

The most common adverse reactions (≥20% in any study) are peripheral neuropathy, fatigue, nausea, diarrhea, neutropenia, upper respiratory tract infection, pyrexia, constipation, vomiting, alopecia, decreased weight, abdominal pain, anemia, stomatitis, lymphopenia, mucositis, thrombocytopenia, and febrile neutropenia.

DRUG INTERACTIONS

Concomitant use of strong CYP3A4 inhibitors has the potential to affect the exposure to monomethyl auristatin E (MMAE). Closely monitor adverse reactions.

USE IN SPECIAL POPULATIONS

Lactation: Breastfeeding is not recommended during ADCETRIS treatment.

Females and Males of Reproductive Potential: Advise females to report pregnancy immediately and advise males with female sexual partners of reproductive potential to use effective contraception during ADCETRIS treatment and for 6 months after the last dose of ADCETRIS.

Please see full Prescribing information, including BOXED WARNING, for ADCETRIS here.

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