Phase 1/2 Study of the Timing and Efficacy of 3 mg Peg-GCSF in Neo/Adjuvant Dose Dense Breast Cancer Treatment Protocols

Abstract

Amol Patel

Background Peg-GCSF has similar efficacy at a dose of 60 µg/kg and 100 µg/kg. The conventional 6 mg SC dose was based on the maximum tolerable dose. In Japan, 3.6 mg dose was approved on the basis of dose finding studies. Peg-GCSF is an integral part of dose-dense chemotherapy protocols. Dose finding and scheduling study of peg-GCSF have not been conducted in Indian patients.

Materials and Methods We conducted two-center phase 1/2 clinical study addressing the timing and efficacy of peg-GCSF in Indian breast cancer patients (CTRI no: 2021/07/034751). Three groups of timing administration were studied, namely 1, 6, and 24 hours post chemotherapy. The phase 2 part was the expansion of the best timing group. The primary objective was dose density, which was defined as receiving chemotherapy on < 3 days of scheduled date. Adriamycin/epirubicin cyclophosphamide (AC/EC) was administered q2 weeks. The total leucocyte (TLC) and absolute neutrophil (ANC) kinetics were studied. Other outcomes were incidence of grade 4 neutropenia, febrile neutropenia (FN), and requirement of additional doses of G-CSF. Bone pain, fever, and myalgia were studied for adverse effects.

Results From November 20 to December 21, 36 patients were enrolled. Patient characteristics are depicted in Table 1. Initially, three patients received the peg-GCSF in each timing group. One patient in each 1-hour and 6 hours needed G-CSF support for maintaining the dose density. The 24-hour group was carried to phase 2 part. Dose density was maintained in 97% of patients. None of the patient in 24-hour group had FN. Also, 4/30 patients had grade 4 neutropenia and required an additional dose of GCSF. Grade 3 or 4 bone pain was not noticed by any of the patients. During the first cycle, the mean ANC (cells/μL) was 5284, 20704, 3010, 6954 on D0, D + 3, D + 7, and D + 13, respectively (Fig. 1A-TLC and 1B-ANC). The mean ANC (cells/μL) rise on D + 3 in cycles 1, 2, 3, 4 was 23810, 29209, 32428,22455, respectively.

Conclusion Dose density of AC/EC breast cancer protocol is maintained with peg-GCSF 3 mg. Post chemotherapy 24-hour timing of peg-GCSF administration remains as the standard. A phase 3 trial of 6 mg versus 3 mg is warranted.

 

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Keywords

3 mg - dose dense protocol - Indian patients - pegylated GCSF - phase 2 study

Background

The granulocyte colony stimulating factor (G-CSF) is in common use for the last 30 years. They are used commonly for the prevention and treatment of febrile neutropenia (FN)[1] and also for mobilizing the harvest before stem cell transplant. The use of these factors is increased remarkably over the last one decade after the dose-dense protocol in adjuvant or neoadjuvant breast cancer treatment became the standard of care for maintaining the dose density.[2] [3] [4] The pegylated-GCSF (Peg-GCSF) was introduced into clinical practice in 1999 and has changed the conventional practice of use of daily GCSF.[5]

The dose of 100 μg/kg of Peg-GCSF was based on phase 1 pharmacokinetic study in mice and human volunteers of age 18 to 45 years. The median absolute neutrophil count (ANC) max (×10⁶/mL) was 30.4, 31.2, 36.7, and 50.8 with doses of 30, 60, 100, and 300 μg/Kg, respectively.[5] Similarly, the median duration of response in days (range) was 5.79 (4.75–9.88), 8.79 (3.83–13.9), 8.29 (4.67–8.92), 8.79 (6.83–13.8) for 30, 60, 100, and 300 μg/kg, respectively. There was no significant difference between 60 μg/kg and 100 μg/kg for ANCmax. The duration of response was better with 60 μg/kg. The kinetics studies of G-CSF have shown that the duration of response might not prolong with increasing doses. The adverse effects of Peg-GCSF are fever, bone pain, and muscle pains. Bone pain has been reported in 25 to 60% of patients. The life-threatening adverse effects such as splenic rupture is rare but of real-world concern.[6] The use of colony-stimulating factors is also associated with significant risk of secondary malignancies especially for acute myeloid leukemia and myelodysplastic syndromes.[7]

Apart from the above known common side effects of G-CSF, there have been several reports of acute respiratory failure during G-CSF-induced neutropenia recovery.[8] It is believed to enhance cytokine production and activate the oxidative burst within circulating or resident alveolar neutrophils and macrophages leading to lung damage. During and postCOVID-19 pandemic, these risks are to be addressed.[9] De-escalating the dose might prevent such complications.

In Japan, peg-GCSF has been approved at a dose of 3.6 mg.[10] The dose finding study on GCSF and/or peg-GCSF has not been conducted in Indian patients. The average weight of Indian females is around 20 kg lesser than their western counterparts. With this background, we hypothesized that reduction of dose to half will not affect the neutrophil recovery and it will maintain the dose intensity chemotherapy protocol in breast cancer patients. The timing of peg-GCSF post chemotherapy has lacuna in the literature.[11]

A phase 1/2 study has been designed to test the timing, safety, tolerability, and efficacy of a lower dose of peg-GCSF (3 mg) in patients who are receiving chemotherapy with dose dense adriamycin/epirubicin cyclophosphamide (dd-AC/EC) protocol. Side effects of peg-GCSF would reduce and there is a scope of reducing financial burden of health care.

 

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Materials and Methods

This phase 1/2 trial was conducted at two centers of armed forces hospitals located in Mumbai (Center A) and Kolkata (Center B). The trial was registered at the Clinical Trial Registry India (CTRI 2021/07/034751). All patients were informed about the procedure and written informed consent was obtained. The Helsinki code of ethical conduct was followed.

Objectives of the Study

The primary objective of the study was to maintain dose intensity, and a delay in scheduled day of chemotherapy > 3 days was considered as an event. Secondary objectives were to analyze the total leucocyte count (TLC) and ANC kinetics, side effects profile will be as per the common terminology criteria for adverse event (CTCAE) version 4[12] to estimate the incidence of FN and the need of additional dose of G-CSF and grade 3 and 4 neutropenia.

 

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Patients

All consecutive patients were enrolled after establishing the early and locally advanced breast cancer diagnosis. Staging work up was done as per the institutional protocol. The study started after obtaining the ethics committee approval and study registration. Inclusion criteria were patients having ECOG Performance status < 2, age of 18 to 75 years, adequate baseline bone marrow function reflected as hemoglobin > 8 g/dL, TLC > 3,500/mm³, ANC > 1,500/mm³), and platelets >100,000/mm³, serum creatinine < 1.5 mg/dL, serum bilirubin < 3 mg/dL, liver enzymes (AST and ALT) within 3 times the upper normal limit. Patients must not have exposed to previous chemotherapy and have active autoimmune disease. Exclusion criteria were lactating and pregnant women, history of previous carcinoma in last 5 years and active hepatitis B, C, or HIV infection. Echocardiography was done for all patients before the start of chemotherapy.

 

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Peg-GCSF

The 6 mg/0.6 mL peg-GCSF pre-filled syringe was used. The pre-filled syringe was emptied in insulin syringe (1 mL) until the 0.3 mL mark. Next, 3 mg of peg GCSF was administered by insulin syringe. A vial of 6 mg was used as per the availability at Center A. The enrolled patients received peg-GCSF 3 mg on as per timing group. Peg-GCSF was administered after 1 hour, 6 hours, and 24 hours of chemotherapy completion. After assessment of the response in nine patients, the second part of the study conducted as phase 2 design and 30 consecutive patients were enrolled. One hour and 6-hour groups were studied at centers A and B, respectively. The 24-hour group was studied at both centers.

 

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Chemotherapy

Dose dense adriamycin (60 mg/m²) cyclophosphamide (600 mg/ m²) (AC) and epirubicin (90 mg/m²) cyclophosphamide (600 mg/m²) (EC) every 2 weeks for four cycles were allowed at standard doses at the discretion of treating medical oncologists.

 

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Procedures

Initially, three patients were studied for pharmacokinetics of peg-GCSF in each 1-hour, 6-hour, and 24 -hour group. Complete blood count was monitored on D + 0, D + 3, D + 7, and D + 13. Patients having ANC below 500/mm³ were treated with additional doses of GCSF for maintaining the dose density. During weekly paclitaxel, CBC monitored weekly, one day prior of chemotherapy and no peg-GCSF was used unless indicated.

Fever in neutropenic (ANC < 500 cells/mm³) patients was defined as a single oral temperature of ≥ 38.3°C (101°F) or a temperature of ≥ 38.0°C (100.4°F) sustained over a 1-hour period.[1] The total leucocyte count measured by an autoanalyzer and whenever required counts were confirmed by slide method.

 

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Statistics

As per the pharmacokinetic study stated above, we hypothesized that 3 mg of peg-GCSF will be equivalent to 6 mg peg-GCSF with a margin of 5%. Also, 3 mg dose was chosen for ease of administration and round off as compared to 3.6 mg considering the average weight of Indian breast cancer patients is below 60 kg. Next, 95% of patients completed the assigned dose dense protocol on or within 2 days of the scheduled date. This assumption is based on previous established literature.[2] The relative dose intensity has been used as the primary outcome in a previous study.[10] The rate of grade 4 neutropenia in the Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741 was 6% in dose dense trial. The treatment delays were 6% in dose dense arm, and 15% were attributed to hematological toxicities.[2] In the landmark trial of adjuvant weekly paclitaxel (dose dense), all 12 doses were permitted to complete within 15 weeks from the initiation of Taxane therapy, considering holidays, vacation, and toxicities.[13] Descriptive statistics was used to study the variables. The association of variables was studied by Chi-square test or Fisher's exact test wherever needed. STATA statistical software version 13 was used for data analysis. Phase 1 patients were planned to include in the combined analysis.

 

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Sample Size

For alpha error of 0.05, beta error of 80%, and the largest response probability of 95% for phase 2 design (Fleming's phase II procedure), a predetermined sample size of 30 was considered adequate.

 

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Safety Monitoring

If rates of FN exceeded > 5% at 3 months or at 25% accrual, the trial would have stopped.

 

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Results

This study was conducted at two centers of armed forces hospital located in Mumbai and Kolkata from July 2021 to December 2021. The baseline characteristics of patients are depicted in [Table 1]. All patients were female with a median age of 50 years (range: 31–72).

Table 1 Baseline characteristics of patients (n = 36)

Variable	N	%
Center*
A	7	19.44
B	29	80.55
Age (y)
Median (range)	50(31-72)
Sex (female)	36	100
Weight
Median (range)	61.3 (47.9-82)
BMI ≥ 25 kg/m2	22	59.46
Weight > 60 kg	18	50
Menopausal status
Pre	14	37.84
Peri	2	5.4
Post	20	54.05
Comorbidities
DM2	3	8.33
DM2 + hypertension	1	2.77
Hypertension	1	2.77
Hypothyroidism	1	2.77
Therapy
Adjuvant	16	44.44
Neoadjuvant	20	55.55
Stage
Early	16	44.44
Locally advanced	19	52.77
Oligometastatic	1	2.77
Receptor
ER +/PR+	19	52.77
Her2neu +	0	0
Triple-negative	15	41.66
Chemotherapy		88.88
AC	32
EC	4	11.11
Surgery** (n = 17)
MRM	12	33.33
BCS	5	13.88
Baseline
Median (range)
Hb (gm/dL)	11.45 (8.5-13.5)
Platelet count (lakh/mm )	2.43 (0.72-5.12)
Total proteins (g/dL)	7.55 (5.9-9.1)
Albumin (g/dL)	4.05 (3-5.2)

^* Centre A – located at Mumbai, B at Kolkata, ** As the study is ongoing, as on 15.1.2022, 17 patients completed surgery, AC/EC: adriamycin epirubicin cyclophosphamide, ER: estrogen receptor, PR: progesterone receptor.

Outcomes

In phase 1 part, one patient each in 1-hour and 6-hour groups had grade 4 neutropenia and none in the 24-hour group. Then, six patients in the 24-hour group and one patient had grade 4 neutropenia. Then, the 24-hour group was expanded as phase 2 part.

Primary objective (maintenance of dose density) – In all patients, dose density was maintained except one patient who received on D + 3 of scheduled day. Another three and two patients received on D + 1 and D + 2 of scheduled date, respectively.

 

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ANC/TLC Kinetics

All four days' kinetics were available for 27 patients and is shown in [Fig 1A] and [1B]. During the first cycle, the mean ANC (cells/μL) was 5,284 (SD 1,616), 20,704 (SD 10,354), 3,010 (SD 2,191), 6,954 (SD 12,050) on D0, D + 3, D + 7, and D + 13, respectively. The mean ANC (cells/μL) on D + 3 in cycles 1, 2, 3, 4 was 23,810, 29,209, 32,428, and 22,455, respectively. All four days and all four cycles information was available for 18 patients and percentile distribution is shown in [Table 2] (box plot distribution is shown in [Fig 2A–D]). A few patients tend to show a remarkable response to peg-GCSF. Such outliers were not studied separately.

Fig. 1 (A) Total leucocyte count: post first chemotherapy cycle (out of 36 patients, 27 had available information on ANC for all days). (B) Absolute neutrophil count: post first chemotherapy cycle (out of 36 patients, 27 had available information on ANC for all days).

Fig. 2 Graphical representation of the distribution of absolute neutrophil count post chemotherapy after peg-GCSF 3 mg administration, A, B, C, D post 1, 2, 3, 4 cycles, respectively.

Table 2 Percentile distribution of ANC in respect of chemotherapy cycles (n = 72 doses, 18 patients)

	Percentile distribution of ANC*
Days of chemotherapy	1%	5%	10%	25%	50% (median)	75%	90%	95%	99%
[#] Cycle 1
D0	2300	2300	2538	4784	5275	5800	8040	8500	8500
D3	2900	2900	3760	9560	23810	29930	30600	34500	34500
D7	90	90	750	1674	2808	3200	7056	9044	9044
D13	1300	1300	2410	3500	3950	5727	7020	54900	54900
Cycle 2
D0	1300	1300	2410	3500	3950	5727	7020	54900	54900
D3	3685	3685	3900	14520	29209	40570	53100	62360	62360
D7	290	290	500	1020	1521	5148	7917	8800	8800
D13	413	413	800	3150	5031	6808	7970	12240	12240
Cycle 3
D0	413	413	720	3100	4385	6120	7970	12240	12240
D3	2925	2925	4980	20839	32428	43470	60630	67193	67193
D7	1150	1150	1300	2240	3583	5313	13400	23800	23800
D13	1200	1200	1700	2260	2818	4420	6310	10440	10440
Cycle 4
D0	1200	1200	1700	2260	2818	4420	6310	10440	10440
D3	4300	4300	4450	7800	22455	46040	52400	57800	57800
D7	786	786	1281	2000	3652	5865	20774	38294	38294
D13	600	600	1780	2900	4611	5530	7030	7770	7770

^* ANC: absolute neutrophil count.

^# Cycle: Adriamycin/epirubicin cyclophosphamide.

 

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Toxic Deaths

No toxic death or treatment-related mortality during this study was seen.

 

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Febrile Neutropenia

One patient had FN in post fourth cycle at center A in the 1-hour group. She had a temperature of 100.4°F and ANC was 120 cells/μL. She recovered with two doses of G-CSF 300 μg over 2 days and received antibiotics as per the institutional policy. None of the patients in the 24-hour group had FN.

 

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Grade 3/4 Neutropenia

In this study, 6/29 patients had grade 3 neutropenia and 4/29 had grade 4 neutropenia.

 

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Requirement of Additional Doses of GSCF

A total of six patients received an extra dose or doses of G-CSF 300 μg. Details of these patients are shown in [Table 3]. At center B, patients were admitted and monitored for ANC. Three patients received the GCSF during second cycles and one patient received during the first cycle. At center B, one patient needed an additional dose of G-CSF during the first cycle. Another patient at center A also received additional two doses of G-CSF in the fourth cycle.

Table 3 Requirement of additional dose of G-CSF for maintaining dose density

Patient	Age	Weight	Centre	Peg-GSCF group	Cycle needing extra dose	extra days G-CSF	Comorbidities
1	50	76	A	1-hour	Fourth	2 days	Hypertension
2	47	48	A	24-hour*	First	2 days	No
3	45	60	B	6-hour	Second	1 day	No
4	61	53	B	24-hour	Second	1 day	No
5	49	77	B	24-hour	Second	4 days	No
6	44	72	B	24-hour	Second	2 days	No

*Patient carried the Peg-GCF-prefilled syringe home, G-CSF: granulocyte colony-stimulating factor, center A–located in Mumbai, B–located in Kolkata.

 

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Discussion

In a retrospective Japanese study of 97 patients of breast cancer treated with dose dense AC protocol, peg-GCSF 3.6 mg prevented the occurrence of FN and maintained a relative dose intensity of 97.9%. In our study, 97.3% of patients completed the assigned treatment in time. The rate of treatment delay by 1 week was seen in a study by Burstein et al in 4.9% of cases though the reasons for delay were not exclusive to hematological toxicity.[14]

Peg-GCSF 3 mg was used in lung cancer in China with positive results in terms of reducing acute lower respiratory tract infection and reducing FN.[15] Similarly, 3.6 mg was used in colon cancer patients treated with the FOLFIRI regimen.[16] Intense chemotherapy protocols, such as docetaxel, adriamycin, and cyclophosphamide (TAC) were studied with 3.6 mg peg-GCSF support and compared with 6 mg. The duration of severe neutropenia was equal in 3.6 and 6 mg groups.[17] Similarly, one large retrospective study from China evaluated the role of 3 and 6 mg peg-GCSF in docetaxel plus cyclophosphamide-treated breast cancer patients. The rates of FN were similar, i.e., 7.3 versus 8.3% in both the groups.[18] There is a prospect of studying the low-dose peg-GCSF in other conditions.

The average weight of females in India, Japan, China, and USA is 52.5, 54.8, 62.2, and 77.1 kg.[19] In a study by Masuda et al on peg-GCSF 3 mg, BSA was 1.55 m² and the body weight was > 60 kg in 38% of cases in the 3.6 mg group.[17] In our study, 50% of patients had a weight of more than 60 (range: 47.9–82) kg. As the primary objective was met, weight in this series would have minimal effect on outcomes. However, this area remains an active field of research in respect of diverse Indian populations and applicability to the western population.

Overall, the rates of FN remain low (1.5–3%) in dose dense protocols.[2] [14] [20] In our study, in the 24-hour phase 2 part, none of the patients had FN. Grade 4 neutropenia of 13% was higher in our patients. The rate of grade 4 neutropenia was 6% in seminal work by Citron et al[2] and grade 3 and 4 neutropenia was 11.8% in a Japanese study.[10] The duration of grade 4 neutropenia usually lasts for ≤ 3 days.[10] [20]

The remarkable higher response to peg-GSCF is not studied in the literature. Such responses are unpredictable. Further studies should analyze such patients separately and long-term follow-up of such patients should be done for the development of bone marrow-related toxicity.

Strength of the Study

For the first time, Indian breast cancer patients were studied systematically for timing and dose of peg-GCSF. All four cycles were analyzed for ANC kinetics for all D0, D + 3, D + 7 and D + 13 days, which are not studied before.

 

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Limitations of the Study

Our study was limited to only breast cancer patients treated with dose dense protocol. The COVID-19 pandemic posed a real challenge to conduct the study. At center A, due to the second peak, enrollment was hampered and a smaller number of patients were recruited. Daily monitoring of counts was not done, which was impracticable during the pandemic. Some patients refused for admission and carried the peg-GCSF at home. It is possible that cold chain might not be maintained during the long 12-hour travel in one patient in the 1-hour group. We expanded the 24-hour group as per our initial experience and available literature. The rates of grade 4 neutropenia appeared to be the same; however, the increase in counts was less in 1-hour and 6-hour groups.

Challenges faced during the conduct of the trial – The majority of patients travelled far distances across the state. The cold chain maintenance is an integral problem in our country. In the 24-hour schedule, travelling to the center is a big hurdle for the conduct of such a trial. Autoinjectors availability would make a change in care of these patients.

 

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Conclusion

Dose density of AC/EC breast cancer protocol is maintained with peg-GCSF 3 mg. Post chemotherapy 24-hour timing of peg-GCSF administration remains as the standard. A phase 3 trial of 6 mg versus 3 mg is warranted.

 

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Conflict of Interest

None declared.

Acknowledgments

We thank all our patients who participated in this study. We also thank Late Prof. Gauri Shankar Bhattacharya who first introduced the low dose concept of Peg GCSF to the first author.

• References

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Artikel online veröffentlicht:
11. August 2023