Interim Phase I Data from Camidanlumab Tesirine (ADCT-301) Shows Encouraging Preliminary Safety and Efficacy Results

Clinical data from two ongoing Phase I clinical trials evaluating camidanlumab tesirine, also known as ADCT-301* or “Cami-T”, in important subtypes of lymphoma and leukemia show encouraging, preliminary, safety and efficacy results.

The data from these clinical trials was presented at the 59th annual meeting of the American Society of Hematology (ASH), held December 9 – 12, 2017 in Atlanta, Georgia (USA).

Mode of Action
Camidanlumab tesirine is an antibody-drug conjugate or ADC, being developed by ADC Therapeutics, comprising a human monoclonal antibody against CD25 (HuMax®-TAC, licensed from Genmab), stochastically conjugated through a dipeptide cleavable linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin with a drug-antibody ratio (DAR) of 2.3 [1][2]

Once bound to a CD25-expresing cell, camidanlumab tesirine is internalized into the cell where enzymes release the PBD-based payload. After internalizing, the released pyrrolobenzodiazepine (PBD) dimer payload, found among the most cytotoxic agents known, binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. [2] In turn, this eventually results in phosphorylation of histone H2AX, cell-cycle arrest in G₂-M, and apoptosis.

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Acute myeloid leukemia is the most common leukemia in the adult population in United States. Patients expressing CD25 on their leukemia cells have a particularly poor prognosis.

Camidanlumab tesirine … has shown an acceptable safety profile…

In vivo, single dose of camidanlumab tesirine leads to dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models.[2]

Attractive target
CD25, also known as interleukin-2 receptor alpha or IL2R-α, a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called interleukin-2 or IL-2, is an attractive target for an antibody-drug conjugate approach as it is expressed on the cell surface of a wide range of hematological malignancies, including Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and diffuse large B-cell lymphoma lymphoma. Interestingly, the expression of CD25 in healthy organs is restricted. [3][4]

To date, camidanlumab tesirine is being evaluated in two ongoing phase Ia/Ib clinical trials in patients with relapsed or refractory Hodgkin lymphoma and non-Hodgkin lymphoma, and in patients with relapsed or refractory CD25-positive acute myeloid leukemia and acute lymphoblastic leukemia. [5][6]

B-cell Hodgkin’s or non-Hodgkin’s lymphoma
The first poster presentation (1510) showed data from 86 evaluable, heavily pre-treated patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit. The median age of patients was 53 years and they had a median of 4 prior therapies.

Data were reported from Part 1 and Part 2 of the Phase I study as of November 1, 2017. In Part 1 (dose escalation), 71 patients were treated at dose ranges from 3-150 µg/kg every three weeks. In Part 2 (dose expansion), 15 Hodgkin Lymphoma patients were treated at 45 µg/kg every 3 weeks. [7]

“Despite considerable advances in the treatment of lymphoma, a significant number of patients still relapse or become refractory to existing therapies and need new treatment options. We are excited by the 77% overall response rate (ORR) in Hodgkin Lymphoma (HL), including a 44% complete response rate,” noted Steven M. Horwitz, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, and Principal Investigator of the study.

“We are also seeing emerging efficacy signals in T-cell lymphomas (ORR: 33%) and B-cell lymphomas (ORR: 19%). Although still early, we are very encouraged by a median duration of response for HL patients of over 5 months to-date. The safety profile appears consistent with what we expect with this target and warhead. We are now working to determine the best dosing regimen for Phase II,” Horwitz added.

Key findings included:

• For the 27 response-evaluable patients with HL in Part 1, treated at doses greater than or equal to 45 µg/kg, the ORR was 77 percent (21/27 patients) with 12 patients achieving a complete response (44%) and 9 patients achieving a partial response (33%).
• For the 12 response-evaluable patients with HL in Part 1 and Part 2, treated at the 45 µg/kg dose, the ORR was 100 percent (12/12) with 6 patients achieving a complete response (50 percent) and 6 patients achieving a partial response (50%).
• For HL patients in Part 1 and Part 2, treated at doses greater than or equal to 45 µg/kg, a complete or partial response was achieved in 21 of 27 patients previously treated with brentuximab vedotin (77%), 13 of 18 patients previously treated with a checkpoint inhibitor (72%), 9 of 14 patients who had previously undergone a stem cell transplantation (64%), and 4 of 8 patients who had previously received all three of these treatments (50%).

Adverse events.
Camidanlumab tesirine has been reasonably well tolerated.

The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients in Part 1 and Part 2 were fatigue (30%), rash (26%), elevated gamma-glutamyltransferase (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse events occurring in at least 5 percent of patients, regardless of attribution, were elevated gamma-glutamyltransferase (13%), reduced platelet count (9%), elevated alanine aminotransferase (6%), anemia (6%), and rash (6%). There were three heavily pre-treated patients diagnosed with auto-immune neurotoxicity, including two patients who developed Guillain-Barré syndrome.

Based on the encouraging preliminary safety and efficacy results, the researchers support further characterization of the dosing regime to optimize the therapeutic window in Hodgkin Lymphoma for a Phase II study.

B-cell acute myeloid leukemia or acute lymphoblastic leukemia
Data were presented from 33 evaluable, heavily pre-treated, patients who had failed, or were intolerant to, any established therapy known to provide clinical benefit.

The median age of patients was 67 years and they had a median of 3 prior therapies.[8]

In Part 1 (dose escalation), 33 patients were treated at dose ranges from 3-92 µg/kg every three weeks, or 30-37.5 µg/kg once weekly.

Key findings:

• One patient achieved a complete response with incomplete blood count recovery;
• Camidanlumab tesirine has shown an acceptable safety profile
• The most common treatment-emergent adverse events of any grade occurring in at least 20 percent of patients were fatigue (30%), nausea (24%), febrile neutropenia (21%), and pneumonia (21%). The most common Grade 3 or 4 adverse events occurring in at least 10 percent of patients, regardless of attribution, were febrile neutropenia (21%), thrombocytopenia (15%), fatigue (12%), reduced neutrophil count (12%), and pneumonia (12%);
• Dose escalation will continue to investigate weekly dosing.

Earlier this year interim results from an ongoing Phase I, open label, dose-escalating study evaluating ADCT-301, for the treatment of relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma, were presented  at the 14th International Conference on Malignant Lymphoma (ICML), held June 14 – 17, 2017 the Lugano Convention Centre, Palazzo dei Congressi, in Lugano, Switzerland, confirming  favorable tolerability and efficacy.

These results were included in a poster showing tolerability, safety, pharmacokinetics and efficacy in patients with relapsed or refractory Hodgkin’s and non-Hodgkin’s lymphoma (r/r HL/NHL). [9]

* Also see: ADC Drug Map