“These interim results from the PROTECTIVE-2 Phase 3 study, which compares the Plinabulin-Neulasta combination to Neulasta alone, have the potential to be clinically meaningful for cancer patients receiving chemotherapy."
Treatment with plinabulin in combination with pegfilgrastim (Neulasta) achieved the primary end point and several key secondary end points in the phase 3 PROTECTIVE (Study 106) clinical trial, which evaluated the combination compared with pegfilgrastim alone for superiority in chemotherapy-induced neutropenia prevention, according to the interim results announced by BeyondSpring, developer of the drug.
These results demonstrate significant enhancement to granulocyte colony-stimulating factors (G-CSFs) with the combination compared with pegfilgrastim alone for the prevention of grade 4 or severe neutropenia, supporting the potential for superiority with the combination compared with pegfilgrastim alone.
“These interim results from the PROTECTIVE-2 Phase 3 study, which compares the Plinabulin-Neulasta combination to Neulasta alone, have the potential to be clinically meaningful for cancer patients receiving chemotherapy,” stated Douglas W. Blayney, MD, professor of Medicine at Stanford Medical School and global principal investigator of Plinabulin’s chemotherapy-induced neutropenia studies. “Since most infections, hospitalizations, and other complications of chemotherapy-induced neutropenia occur in the first week after chemotherapy, it is particularly gratifying to see the combination’s clinical benefit demonstrated.”
The primary end point was the rare of severe neutropenia prevention in cycle 1 (P <.01). The key secondary end points included duration of severe neutropenia in cycle 1 (P <.05) and duration of severe neutropenia in the first 8 days of cycle 1 (P <.05). The achievement of these end points demonstrates the agent’s ability to provide early protection against severe neutropenia induced by chemotherapy.
The interim analysis of the double-blind, active-controlled, global PROTECTIVE-2 study was pre-specified for the first 120 patients accrued. The study also has procedures in place for the prevention of potential bias after the planned interim analysis, and BeyondSpring opted to be informed by independent statisticians on whether the pre-specified P values were met rather than the exact P values.
The study was designed to assess both the safety and efficacy of plinabulin in patients with breast cancer treated with docetaxel, doxorubicin, and cyclophosphamide (TAC) in a 21-day cycle. Plinabulin was administered in a 40 mg dose on day 1 with a 6 mg dose of pegfilgrastim on day 2, while pegfilgrastim was administered at the same 6 mg dose on day 2 in the control arm. TAC is considered a high-risk chemotherapy regimen associated with neutropenia.
PROTECTIVE-2 is a superiority study for chemotherapy-induced neutropenia efficacy compared with pegfilgrastim alone and is currently enrolling patients. Grade 4 neutropenia rate for TAC and pegfilgrastim is observed in 83% to 93% of patients, which represents a severe unmet medical need.
The study drug and G-CSF have complementary mechanisms of action for preventing chemotherapy-induced neutropenia. Plinabulin is a first-in-class differentiated immune and stem cell modulator, which is currently in late-stage clinical development as a potential treatment for increasing overall survival in patients with cancer in addition to its ability to alleviate chemotherapy-induced neutropenia.
Plinabulin is also under evaluation in a phase 3 study as a direct anticancer drug as treatment of patients with non–small cell lung cancer and 2 phase 3 studies for the prevention of chemotherapy-induced neutropenia. The data for this agent in preventing chemotherapy-induced neutropenia highlights its ability to boost the number of hematopoietic stem or progenitor cells (HSPcs), as well as lineage-/cKIT+/Sca1+ cells in mice. Plinabulin’s effects on HSPcs may explain its ability to treat chemotherapy-induced neutropenia as well as its ability to reduce chemotherapy-induced thrombocytopenia and increase circulating CD34-positive cells.
To be included in the study, patients should be candidates for TAC in either the adjuvant or neoadjuvant setting, have early-stage breast cancer, and have received no prior chemotherapy. Patients must also have an ECOG performance status of 0 or 1 and a life expectancy of at least 3 months. Patients cannot be included in the study if they have a history of myelogenous leukemia, myelodysplastic syndrome, or sickle cell disease; use of CYP3A4, CYP2D6 or P-glycoprotein inhibitors and inducers within 14 days prior to receiving the study drug; or have received an investigational agent or tumor vaccine within 2 weeks, any concurrent anticancer therapies, or a bone marrow or stem cell transplantation.
“These results could help to confirm the patient benefit of Plinabulin’s different mechanism of action from the G-CSF-based agents, such as Neulasta,” Blayney stated. “Plinabulin appears to have chemotherapy-induced neutropenia protection in Week 1, and G-CSFs have protection in Week 2 of chemotherapy cycles. The combination should logically provide significantly better protection than Neulasta alone as shown in the interim readout. We are well on our way to confirming that the combination offers protection throughout the chemotherapy cycle, which is an unmet medical need.”
BeyondSpring Announces Positive Topline Interim Results from PROTECTIVE-2 (Study 106) Phase 3 Trial Evaluating Superiority of Plinabulin in Combination with Neulasta for Chemotherapy-Induced Neutropenia Prevention. News Release. BeyondSpring. June 15, 2020. Accessed June 15, 2020. https://bit.ly/2YDJbiQ