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BeyondSpring : Study 106 Phase 2 Summary

04/30/2020 | 07:48am

MAY 2020



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CIN indication

Broad label: for all chemo and all cancer

Plinabulin is indicated for concurrent administration with a

myelosuppressive chemotherapeutic regimen in patients with non- myeloid malignancies for the prevention of chemotherapy induced neutropenia


Plinabulin Study BPI-2358-106 (106)

  • A Phase 2/3, Multicenter, Randomized Study to Evaluate Plinabulin versus Pegfilgrastim in Prevention of Severe Neutropenia in

Breast Cancer Patients Receiving Myelosuppressive Chemotherapy with

Docetaxel, Doxorubicin, and Cyclophosphamide (TAC) (Protective 2)

Designed to demonstrate the superiority of Plinabulin 40 mg + 6 mg Pegfilgrastim compared to 6 mg

Pegfilgrastim alone.


Literature on prevention of grade 4


correlates with a tangible reduction

in the risk of infection


Grade 4 neutropenia incidence - directly linked to infection risk (Body 1966)

The figures demonstrates that at ANC 100-500/mm3 (or 0.1-0.5 x 109 cells/L; grade 4 neutropenia), there is a high

percentage of patients with infection, number of episodes of severe infection

At levels of > 1000 mm3 (or 1 x 109 cells/L, < grade 3 neutropenia), the infection rate fell to a minimum plateau

Fig. 1 The effect of granulocyte level on the

Fig. 2. The frequency of infectious episodes

presence of identified infection

related to the granulocyte level

Bodey GP et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64(2): 328-40


Low Neutrophil count directly links to Infections (Sickles 1975)

A clear trend in that as AGC decreases, infections increase especially in fever and bacteremia

  • By comparing incidences of symptoms and signs in select patient populations differing only with respect to absolute granulocyte counts (AGC), we have demonstrated a strong influence of increasing levels of granulocytopenia on the clinical presentation of infection"(344 infections in a select group of cancer patients experiencing substantial myelosuppression).

Sickles EA et al. Clinical presentation of Infection in granulocytopenic patients . Arc Intern Med 1975; 135: 715-9


Lower neutrophil count links to more fever and FN (Bodey 1978)

  • All of the febrile episodes occurring in 494 adults with acute leukemia were reviewed at MD Anderson hospital between
    1966-1972. The patients spent 28% of their days in the hospital with fever. Sixty-four percent of the febrile episodes were due to infection
  • Fever occurred in 48% of the episodes when the ANC count was < 0.1 x 10^9 cells/L and 70% of the febrile episodes occurred when the ANC < 0.5 x 10 ^9 cells/L (grade 4)
  • The proportion of febrile episodes due to infection was related to the number of circulating neutrophils. Infection was proven to be the cause of fever most often in patients with severe [grade 4] neutropenia
  • In Bodey's table 9, the ANC was determined on the day of onset of each episode of fever

Bodey GP et al. Fever and infection in leukemic patients: a study of 494 consecutive patients. Cancer 1978; 41(4): 1610-22


Association between baseline grade 4 neutropenia & development of fever, documented infection or bacteremia (Buckley 2014)

"Kaplan-Meier estimates of the freedom from fever, documented infection, and bacteremia in our cohort for patients presenting with grade 4 neutropenia (i.e., ANC <500 cells/mL) versus those presenting with higher ANC, from the first day of induction chemotherapy until day 35; patients who received salvage chemotherapy were censored on the first day of initiation of such therapy".

Grade 4 neutropenia was associated with fever (p=0.04), documented infection (p<0.0001), and bacteremia (p=0.002)

Buckley SA et al. Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high-grade myelodysplatic syndromes. American J. Hematology 2014; 89(4): 423-28.


Low neutrophil count linked to fatality rate (Bodey 1966)

The fatality rate from severe infections is also related to ANC number (or severe neutropenia)

during the first week of infection as reported in Table 1 from Body

Bodey GP et al. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64(2): 328-40


Literature that supports grade 4 neutropenia correlation with high rate of infection, bacteremia infection, fever and mortality

Relationship of decrease of neutrophils to the increase risk of infection

Bodey 1966: Grade 4 Neutropenia Incidence - Directly linked to infection risk

Bow 2013: ANC inversely related to the risk of invasive infection especially Grade 4

Bow 2013: The magnitude of the physical signs of inflammation and infection are directly related to ANC.

Relationship of decreased neutrophils and the increase risk of infection, fever and bacteremia infection

  • Bow 2009: Majority of febrile episodes and documented infections observed at <= Grade 4
  • The risk for bacteremic infections increase significantly as ANC falls < 0.1 X 109/L
  • Sickels 1975: Demonstration of a strong influence of increasing levels of granulocytopenia on the clinical presentation of infection and, fever and bacteremia
  • Bodey 1978: Relationship of decreased neutrophils and the proportion of febrile episodes and infection
  • Buckley 2014: Grade 4 neutropenia - a risk factor for infection-associated AE

Relationship of severe neutropenia to mortality

  • Body 1966: Decreased neutrophils to increased mortality

Bow EJ. Neutropenic Fever Syndrome in Patients undergoing Cytotoxic Therapy for Acute Leukemia and Myelodysplatic Syndrome. Seminars in Hematology 2009; 46(3): 259-68

Bow EJ. Infection in Neutropenic Patients with Cancer. Crit Care Clin 2013; 29: 411-41.


Study 106 Phase 2 data summary


Study 106 Phase 2: Phase 3 dosage selection (20 mg/m2)

93 patients used Plinabulin, which fully showed that Plinabulin protects ANC in the 1st week after

chemotherapy; pegfilgrastim protects neutrophils in the 2nd week

Median absolute neutrophil (ANC) monotherapy (1st cycle) Plinabulin vs. pegfilgrastim (log scale)

Median of absolute neutrophils (ANC) in

combination therapy (1st cycle)

Plinabulin/pegfilgrastim vs. pegfilgrastim (log scale)

Black: pegfilgrastim6.0 mg Green: Plinabulin 30 mg/m2 Red: Plinabulin20 mg/m2 Blue: Plinabulin 10 mg/m2

Black: pegfilgrastim 6.0 mg

Green : Plinabulin20mg/m2 + 6.0 mg pegfilgrastim Red: Plinabulin20 mg/m2 + 3.0 mg pegfilgrastim Blue: Plinabulin20 mg/m2 + 1.5 mg pegfilgrastim


Study 106 Phase 2: Plinabulin's protection of neutrophil for the first 8 days is significantly better than that of pegfilgrastim

Pegfilgrastim group (group 1): all grade 4 neutropenia occurs on days 1-8, starting from day 9, without any grade 4 neutropenia

Plinabulin (single or combined, group 2-7): Plinabulin, protects ANC on days 1-8, so as long as there is Plinabulin, the proportion of grade 4 neutropenia is between 1-8 days are about 47% smaller than that of Pegfilgrastim (statistically significant)

Day 1-8


p value


Grade 4

Without grade 4


(CMH methods)

pegfilgrastim 6 mg




(group 1)








(group 2-7)



(vs. group 1)

Plinabulin 20 mg/m2





(group 3, 5-7)



(vs. group 1)

Plinabulin 20 mg/m2 +



pegfilgrastim 6mg (group






Study 106 Phase 2: superior in the absence of grade 4 or grade 3/4 neutropenia

No grade 4 neutropenia: no infection, fever, FN, bacteremia, and death

No grade3/4 neutropenia: no need to reduce chemotherapy dose and other 4Ds, to affect the efficacy of chemotherapy

Breast cancer patients-TAC



Study 106, Phase 2 data


Treatment regimen





+ Plinabulin

Number of patients (n)





Grade 3/4 neutropenia





Grade 4 neutropenia





Without grade 3/4 neutropenia









Without grade 4 neutropenia









ANC nadir





  1. Masuda N et al. Support Care Cancer 23(10): 2891-8 (2015); 2. Lee J et al. Ann Surg Treat Res 94(5): 223-8 (2018);
  1. Bodey GP et al. Ann Intern Med 64(2): 328-40 (1966); Crawford J et al. Cancer 10(2): 228-237 (2004)



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