Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Blood and Lymph Conditions

Rare Diseases

Breast Neoplasms

Neutropenia

Breast Diseases

Skin Diseases

Agranulocytosis

Leukopenia

Cytopenia

Hematologic Diseases

Leukocyte Disorders

Granulocytopenia

All Drugs and Chemicals

Lenograstim

During each chemotherapy cycle eligible patients receive LA-EP2006 s.c. post chemotherapy application.

During each chemotherapy cycle eligible patients receive Neulasta® s.c. post chemotherapy application.

Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle LA-EP2006 is injected s.c. post chemotherapy application.

LA-EP2006

Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle Neulasta® is injected s.c. post chemotherapy application.

Neulasta®

Sandoz Biopharmaceutical Clinical Development

The study will assess the efficacy of LA-EP2006 compared to Neulasta® with respect to the mean duration of severe neutropenia during treatment with myelosuppressive chemotherapy in breast cancer patients.

The Pegfilgrastim Randomized Oncology (Supportive Care) Trial to Evaluate Comparative Treatment (PROTECT-2) was a confirmatory efficacy and safety study designed to compare the proposed biosimilar LA-EP2006 with the reference pegfilgrastim in woman with early stage breast cancer receiving (neo)-adjuvant myelosuppressive chemotherapy. Patient received TAC (intravenous docetaxel 75mg/m\^2, doxorubicin 50 mg/m\^2, and cyclophosphamide 500mg/m\^2) on day1 of each cycle, for six or more cycles. A total of 308 patients were randomized to LA-EP2006 (n=155) or reference Neulasta® (n=153). Treatment was given subcutaneously on day 2 of each cycle. The primary end point was the duration of severe neutropenia (DSN) during Cycle 1 (defined as number of consecutive days with absolute neutrophil count \<0.5 × 10\^9 cells/L). LA-EP2006 was equivalent to the reference product in DSN (difference: -0.16 days; 95% CI \[-0.40, 0.08\]). Further, LA-EP2006 and the reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety.

Phase III Study Comparing the Efficacy and Safety of LA-EP2006 and Peg-Filgrastim

Pivotal Study in Breast Cancer Patients Investigating Efficacy and Safety of LA-EP2006 and Neulasta®

Mean duration of severe neutropenia, defined as number of consecutive days with ANC \<0.5 × 10\^9/l (grade 4 neutropenia).

FN was defined as oral temperature ≥ 38.3°C while having an absolute neutrophil count (ANC) \< 0.5 × 10\^9 cells/L. Serious treatment-emergent adverse events (TEAEs) were reconciled with the fever and ANC results recorded in the patient diary and CRF and therefore only the serious TEAEs of FN ("febrile neutropenia", "neutropenic sepsis") were taken into account.

Fever was defined as an oral body temperature of ≥ 38.3°C. Fever episodes were described by maximum oral temperature and the number of patients who had fever at least once.

The depth of ANC nadir was defined as the patient's lowest ANC (10\^9 cells/L) in Cycle 1.

Numbers of patients with ANC nadir based per day during Cycle 1 are given.

Time to absolute neutrophil count (ANC) recovery was defined as the time in days from ANC nadir until the patient's ANC had increased to ≥ 2 × 10\^9 cells/L after the nadir in Cycle 1.

The number of patients with infections was recorded for each cycle and across all cycles. Infections were identified by the AE documentation page selecting all events coded with System Organ Class "Infections and Infestations".

Number of patients with death due to infections

Sandoz GmbH

Sandoz

Severity of treatment-emergent adverse events (TEAEs) was captured by CTCAE (Common Toxicology Criteria for Adverse Events) grading. SAF set = safety analysis set was used

During each chemotherapy cycle eligible patients receive LA-EP2006 s.c. post chemotherapy application.

LA-EP2006: Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle LA-EP2006 is injected s.c. post chemotherapy application.

During each chemotherapy cycle eligible patients receive Neulasta® s.c. post chemotherapy application.

Neulasta®: Eligible patients are scheduled to receive six cycles of chemotherapy every three weeks. During each chemotherapy cycle pegfilgrastim is injected s.c. post chemotherapy application.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

The 2 patients with race "More than one race" were reported as Hispanic origin.

Race (NIH/OMB)

For 2 patients in the Neulasta treatment group, the date of initial diagnosis was incomplete.

Time since diagnosis

TNM Disease stage was defined according to the American Joint Committee on Cancer (AJCC): (I) = T1 N0 M0 / T0 N1mi M0 / T1 N1mi M0; (II) = T0 N1 M0 / T1 N1 M0 / T2 N0 M0 / T2 N1 M0 / T3 N0 M0; (III) = T0 N2 M0 / T1 N2 M0 / T2 N2 M0 / T3 N1 M0 / T3 N2 M0 / T4 N0 M0 / T4 N1 M0 / T4 N2 M0 / AnyT N3 M0; (IV) = AnyT AnyN M1; T: size or direct extent of the primary tumour; N: degree of spread to regional lymph nodes; N1mi: Micrometastases (\> 0.2 mm and/or \> 200 cells, but none \> 2.0 mm); M: presence of distant; https://www.cancer.gov/types/breast/hp/breast-treatment-pdq#link/_27

Disease stage

Previous breast cancer surgery

Previous radiotherapy

Grading according to ECOG:

0: Fully active, able to carry on all pre-disease performance without restriction 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2: Ambulatory and capable of all self-care but unable to carry out any work activities up and about more than 50% of waking hours 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

ECOG performance status

Strategic Planning, Biopharmaceutical Clinical Development

The primary objective of the study was to compare LA-EP2006 and Neulasta in terms of the DSN in Cycle 1. It was to be shown in a hierarchical way:

1. that LA-EP2006 is equivalent (margin: ±1 day) to Neulasta® with respect to DSN duration in Cycle 1 and, if this was successfully established,
2. that LA-EP2006 is non-inferior (margin: -0.6 days) to Neulasta® with respect to DSN duration in Cycle 1.

Missing patients in FAS set due to blind data review meeting decision (no ANC profiles available). FAS set = full analysis set; PP set = per protocol set

Mean Duration of Severe Neutropenia (DSN) During Cycle 1 of Chemotherapy

Cycle 1

Cycle 2

Cycle 3

Cycle 4

Cycle 5

Cycle 6

All cycles (at least on incidence)

Incidence of Febrile Neutropenia (FN)

Overall

Patients with more than 1 event during the study (overall) are counted only once. FAS set = full analysis set

Number of Patients With at Least One Episode of Fever by Cycle and Across All Cycles

Depth of ANC Nadir in Cycle 1

Days 1-5

Day 6

Day 7

Day 8

Day 9

Days 10-15

not definable

Number of Patients With ANC Nadir Per Day in Cycle 1

Time to ANC Recovery in Days in Cycle 1

Frequency of Infections by Cycle and Across All Cycles

Mortality Due to Infection

Overall Study

Anemia

Participants will receive roxadustat as an oral tablet, 3 times per week (TIW) for up to a maximum of 16 weeks.

Roxadustat will be administered per schedule specified in the arm description.

Roxadustat

The purpose of this study is to find out if roxadustat (also known as FG-4592) is safe and effective for the treatment of anemia in participants receiving chemotherapy treatment for cancer.

This study consists of three periods:

1. Screening Period up to 28 days
2. Treatment Period of up to16 weeks
3. A Follow-up period of 4 weeks.

Evaluation of Efficacy and Safety of Roxadustat for the Treatment of Chemotherapy Induced Anemia

A Phase 2 Open Label Study Investigating the Efficacy and Safety of Roxadustat (FG-4592) for Treatment of Anemia in Patients Receiving Chemotherapy Treatment for Non-Myeloid Malignancies

Baseline Hb was defined as the mean of the assessments from central lab prior to first dose of the study treatment, which included up to 2 latest screening values prior to Day 1 and a value on Day 1. All central lab assessments from Day 1 to end of treatment (EOT) or early termination (ET) were included in the evaluation of this endpoint. Hb values within 4 weeks after an RBC transfusion were excluded.

Baseline Hb was defined as the mean of the assessments from central lab prior to first dose of the study treatment, which included up to 2 latest screening values prior to Day 1 and a value on Day 1. Mean Hb during treatment was computed using the mean area-under-the-curve trapezoid method, from Day 1 to EOT or ET Hb assessment.

Baseline Hb was defined as the mean of the assessments from central lab prior to first dose of the study treatment, which included up to 2 latest screening values prior to Day 1 and a value on Day 1.

The 95% confidence interval (CI) was based on the exact method of Clopper-Pearson method. All central lab assessments from Day 1 to EOT or ET were included in the analysis. Hb values within 4 weeks after an RBC transfusion was excluded.

Median was calculated using Kaplan-Meier product limit method. 95% CI was calculated using the method of Brookmeyer and Crowley. All central lab assessments from Day 1 to EOT or ET were included in the analysis. Hb values within 4 weeks after an RBC transfusion were excluded.

The 95% CI was based on the exact method of Clopper-Pearson method. All central lab assessments from Day 1 to EOT or ET were included in the analysis. Hb values within 4 weeks after an RBC transfusion was excluded.

Hematopoietic response was defined as an increase in Hb of 1.5 g/dL from baseline or attaining a Hb of 11 g/dL. The 95% CI was based on the exact method of Clopper-Pearson method. All central lab assessments from Day 1 to EOT or ET were included in the analysis. Hb values within 4 weeks after an RBC transfusion was excluded.

AstraZeneca

Astellas Pharma Inc

FibroGen

Safety population included all participants who took at least 1 dose of study medication.

Participants received roxadustat as an oral tablet, TIW for up to a maximum of 16 weeks. The starting dose of roxadustat was 2.0 mg/kg. The dose was updated with Amendment 3 (dated 22 May 2020) for newly enrolled participants by 1 level that is, from 2.0 mg/kg to 2.5 mg/kg level to achieve an improved Hb response.

Race/Ethnicity, Customized

Baseline Hemoglobin (Hb)

Intent-to-treat (ITT) population included all participants enrolled in the roxadustat treatment period and received at least 1 dose of study medication.

Clinical Trial Information Desk

Full analysis set included all enrolled participants who received at least 1 dose of roxadustat, had a baseline Hb and at least 1 central lab Hb assessment during the treatment period.

Maximum Change in Hb Within 16 Weeks From Baseline Without Red Blood Cell (RBC) Transfusion

Mean Change in Hb Level From Baseline to Week 16 (Without RBC Transfusion)

Change at Week 9

Change at Week 13

Change at Week 16

Full analysis set included all enrolled participants who received at least 1 dose of roxadustat, had a baseline Hb and at least 1 central lab Hb assessment during the treatment period. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.

Change in Hb From Baseline at Weeks 9, 13, and 16 (Without RBC Transfusion)

Percentage of Participants Who Achieved a ≥1 g/dL Increase in Hb From Baseline Through Week 16

Time to Achieve a ≥1 g/dL Increase in Hb From Baseline Through Week 16

Percentage of Participants Who Achieved a ≥1.5 g/dL Increase in Hb From Baseline Through Week 16

Percentage of Participants Who Achieved a Hematopoietic Response

Percentage of Participants Who Achieved a ≥2 g/dL Increase in Hb From Baseline Through Week 16

Full analysis set included all enrolled participants who received at least 1 dose of roxadustat, had a baseline Hb and at least 1 central lab Hb assessment during the treatment period. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Percentage of Participants Who Had an RBC Transfusion From Beginning of Week 5 (Day 29) to Week 16

Participants received roxadustat as an oral tablet, 3 times per week (TIW) for up to a maximum of 16 weeks. The starting dose of roxadustat was 2.0 milligrams (mg)/kilogram (kg). The dose was updated with Amendment 3 (dated 22 May 2020) for newly enrolled participants by 1 level that is, from 2.0 mg/kg to 2.5 mg/kg level to achieve an improved hemoglobin (Hb) response.

Infections

Symptoms and General Pathology

Wounds and Injuries

Behaviors and Mental Disorders

Communicable Diseases

Hyperthermia

Fever

Febrile Neutropenia

Disease Attributes

Body Temperature Changes

Stress Disorders, Traumatic

Heat Stress Disorders

L. Smeele, Professor, MD

Febrile neutropenia (FN) is a clinically important adverse effect of myelosuppressive chemotherapy. If patients present with FN, attention is focussed on well-recognized sites of origin of infection: the airways, urinary tracts, and skin. However, infections can be only documented clinically in about two-third of febrile episodes, whereas a causative microbial pathogen cannot be identified in the majority (\>70%) of cases.

Pre-treatment oral evaluation aimed to identify and eliminate oral/dental foci is only routinely used in patients at high risk for oral complications (i.e. head and neck cancer patients and stem cell transplantation recipients). However, any patient treated with myelosuppressive chemotherapy, be it for cure or palliation, is at risk of developing infection in and/or originating from the oral cavity. Nevertheless, in these patients dental screening is somewhat randomly employed at the oncologist's discretion.

More insight into the pre-treatment oral condition and its potential role in FN is mandatory, particularly considering the growing numbers of older patients retaining their natural dentition and the increase of dental diseases and cancer incidence with age.

In addition, oral diseases may aggravate chemotherapy-induced oral mucositis (OM). OM is associated with an inflammatory response, which together with ulcerations providing a portal of entry for bacteria, can result in FN and systemic inflammatory syndrome (SIRS) and/or sepsis. Evidence suggests that microorganisms are involved in the pathobiology of OM, but no longitudinal studies using open-end sequencing are available.

Furthermore, comparing bacteria identified in blood cultures in febrile patients with those of the oral cavity will expand the knowledge on the role of the oral cavity as a potential source of bacteremia.

The investigators expect that the results will provide a scientific base for subsequent intervention studies on the efficacy of dental screening and elimination of foci, and other interventions aimed at modifying the oral environment before and during chemotherapy.

The Oral Cavity as a Source of Febrile Neutropenia

The Oral Cavity as a Source of Febrile Neutropenia: An Observational Study in Cancer Patients Treated With Myelosuppressive Chemotherapy

Score Clinical criteria for the score per sextant (note site per sextant with the highest score) 0 No pockets \>3mm in depth, no calculus, no overhanging restorations and no bleeding on probing to the bottom of the pocket

1. No pockets \>3mm in depth, no calculus, no overhangs of restorations, but presence of bleeding on probing to the bottom of the pocket
2. No pockets \>3mm in depth, presence of bleeding on probing to the bottom of the pocket, and presence of calculus or overhanging restorations
3. Presence of pathological pockets of 4-5mm without gingival recession
4. Presence of pathological pockets of 4-5mm with gingival recession
5. Presence of pathological pockets of 6mm or more.

Ref:

Van der Velden U, (2009) J Clin Periodontol. 2009 Dec;36(12):1018-24. doi: 10.1111/j.1600-051X.2009.01495.x.

The Dutch periodontal screening index validation and its application in The Netherlands.

1. no caries
2. caries in enamel
3. caries \<50% in dentin
4. caries \>50% in dentin
5. caries in rootcanal

1. not impacted
2. partially impacted
3. impacted

The plaque index is calculated via the amount of plaque on the mesiobuccal+buccal+distobuccal+mesiopalatinal or mesiolingual+palatinal or lingual+distopalatinal or distolingual of every tooth, given in percentages.

Bone loss is measured on a X-OPT and the average bone loss is noted in millimeters.

Peri-apical radiolucency is diagnosed on a X-OPT or intraoral radiograph and will be noted as

1. yes
2. no

The presence of radix relicta is noted as

1. yes
2. no

The NCI-CTCAE v3.0 mucositis/stomatitis is noted for every patient when visiting the hospital.

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Phd student

Chemotherapy-Induced Febrile Neutropenia

Adjuvants, Immunologic

Immunologic Factors

PegaGen® was injected as a single subcutaneous dose after completion of cytotoxic chemotherapy

Peg-filgrastim

Arash Jenabian, Professor

The present study was an observational, multicenter, non-interventional, single arm, open label, PMS study conducted in Iran.

The primary objective of this study was safety assessment, including the rate of AEs. The secondary objective was the effectiveness evaluation in the prevention of chemotherapy-induced FN.

The present study was an observational, multicenter, non-interventional, single arm, open label, PMS study conducted in Iran.

Data was gathered in two booklets, each containing information on four cycles of chemotherapy, which was filled by the designated physician. The duration of PegaGen® treatment was at the physicians' discretion based on the patient's condition.

The primary objective of this study was safety assessment, including the rate of AEs. The secondary objective was the effectiveness evaluation in the prevention of chemotherapy-induced FN.

This study was single arm and 654 subjects participated across various tumor types and regimens.

Safety and Effectiveness Assessment of PeGagen® (Pegfilgrastim) in the Prevention of Chemotherapy-induced FN

Safety and Effectiveness Assessment of PeGagen® (Pegfilgrastim) in the Prevention of Chemotherapy-induced Febrile Neutropenia in Iranian Cancer Patients

Safety evaluation was reported using summary statistics. For each AE, data was summarized using incidence according to system organ class and preferred term of AEs and SAEs. Moreover, causality assessment was done and its results was reported by frequency and percentage.

The frequency of neutropenia and neutropenic fever was reported

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase III Study Comparing the Efficacy and Safety of LA-EP2006 and Peg-Filgrastim	NCT01516736	Chemotherapy-in... Breast Cancer	LA-EP2006 Neulasta®	18 Years -	Sandoz
Evaluation of Efficacy and Safety of Roxadustat for the Treatment of Chemotherapy Induced Anemia	NCT04076943	Chemotherapy In...	Roxadustat	18 Years -	FibroGen
The Oral Cavity as a Source of Febrile Neutropenia	NCT02702583	Febrile Neutrop... Solid Tumors Dental Infectio... Oral Infection		18 Years -	Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Phase III Study Comparing the Efficacy and Safety of LA-EP2006 and Peg-Filgrastim	NCT01516736	Chemotherapy-in... Breast Cancer	LA-EP2006 Neulasta®	18 Years -	Sandoz
Safety and Effectiveness Assessment of PeGagen® (Pegfilgrastim) in the Prevention of Chemotherapy-induced FN	NCT04460079	Chemotherapy-in...	Peg-filgrastim	18 Years -	Cinnagen

Spots Global Cancer Trial Database for myelosuppressive chemotherapy