Darbepoetin Alfa With or Without Iron in Treating Anemia Caused By Chemotherapy in Patients With Cancer

• ClinicalTrials.gov Identifier: NCT00661999
• Recruitment Status: Completed
• First Posted: April 21, 2008
• Results First Posted: April 18, 2011
• Last Update Posted: May 17, 2011
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by: Mayo Clinic

Study Description

Brief Summary:

RATIONALE: Darbepoetin alfa may cause the body to make more red blood cells. Red blood cells contain iron that is needed to carry oxygen to the tissues. It is not yet known whether giving darbepoetin alfa (DA) together with intravenous iron or oral iron is more effective than giving darbepoetin alfa together with a placebo in treating anemia caused by chemotherapy.

PURPOSE: This randomized phase III trial is studying giving darbepoetin alfa together with iron to see how well it works compared with giving darbepoetin alfa together with a placebo in treating anemia caused by chemotherapy in patients with cancer.

Condition or disease	Intervention/treatment	Phase
Anemia; Leukemia; Lymphoma; Lymphoproliferative Disorder; Multiple Myeloma and Plasma Cell Neoplasm; Precancerous Condition; Unspecified Adult Solid Tumor, Protocol Specific	Biological: darbepoetin alfa; Dietary Supplement: ferrous sulfate; Drug: sodium ferric gluconate complex in sucrose; Other: placebo	Phase 3

Detailed Description:

OBJECTIVES:

Primary

* To compare the effects of IV iron, oral iron, or placebo in combination with darbepoetin alfa on the hematopoietic response rate, defined as a hemoglobin increment of ≥ 2.0 g/dL from baseline or achievement of hemoglobin of ≥ 11 g/dL in the absence of red blood cell transfusions (RBC) in the preceding 28 days of the treatment period, in cancer patients with chemotherapy-associated anemia.

Secondary

• To compare the effects of these regimens on the mean hemoglobin increment from baseline to weeks 7 and 16 in these patients.
• To compare the effects of these regimens on the percentage of patients maintaining an average hemoglobin level within the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO)and National Comprehensive Cancer Network(NCCN) guideline-based target hemoglobin range (11-13 g/dL), once achieving a hemoglobin of ≥ 11 g/dL from week 1 to week 16 in the absence of RBC transfusions in the preceding 28 days of the treatment period.
• To compare the effects of intravenously (IV) iron, oral iron, or placebo on the response to darbepoetin alfa, in terms of time to achieving hemoglobin levels of ≥ 11g/dL.
• To compare the effects of these regimens on the percentage of patients who require RBC transfusions and the total transfusion needs.
• To compare the effects of these regimens on the change in hemoglobin week by week.
• To compare the effects of these regimens on quality-of-life changes from baseline to weeks 7 and 16.
• To identify if patients with inflammation (as indicated by elevated C-reactive protein (CRP) and serum hepcidin levels or low soluble transferrin receptor (sTfR)/log ferritin ratios) respond differently to darbepoetin alfa and iron therapy than patients without inflammation.

OUTLINE: Patients are stratified according to severity of anemia (mild [hemoglobin ≥ 9.5 g/dL] vs severe [hemoglobin < 9.5 g/dL]), treatment with a platinum-containing regimen (yes vs no), and gender. Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive darbepoetin alfa subcutaneously and sodium ferric gluconate complex IV over 90 minutes on day 1.
• Arm II: Patients receive darbepoetin alfa as in arm I and oral ferrous sulfate once daily on days 1-21.
• Arm III: Patients receive darbepoetin alfa as in arm I and oral placebo once daily on days 1-21.

In all arms, treatment repeats every 21 days for up to 15 weeks in the absence of unacceptable toxicity.

Patients complete quality-of-life (QOL) questionnaires in weeks 1, 7, and 16.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 502 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Supportive Care
• Official Title: A Phase III, Randomized Study of the Effects of Parenteral Iron, Oral Iron, or No Iron Supplementation on the Erythropoietic Response to Darbepoetin Alfa for Cancer Patients With Chemotherapy-Associated Anemia
• Study Start Date: January 2006
• Actual Primary Completion Date: March 2009
• Actual Study Completion Date: March 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I; Patients receive darbepoetin alfa subcutaneously and sodium ferric gluconate complex IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 15 weeks in the absence of unacceptable toxicity.	Biological: darbepoetin alfa; Given by injection; Drug: sodium ferric gluconate complex in sucrose; Given by IV
Experimental: Arm II; Patients receive darbepoetin alfa as in arm I and oral ferrous sulfate once daily on days 1-21. Treatment repeats every 21 days for up to 15 weeks in the absence of unacceptable toxicity.	Biological: darbepoetin alfa; Given by injection; Dietary Supplement: ferrous sulfate; Given by mouth
Experimental: Arm III; Patients receive darbepoetin alfa as in arm I and oral placebo once daily on days 1-21. Treatment repeats every 21 days for up to 15 weeks in the absence of unacceptable toxicity.	Biological: darbepoetin alfa; Given by injection; Other: placebo; Given by mouth

Outcome Measures

Primary Outcome Measures :

1. Hematopoietic Response Rate Defined as the Number of Participants Who Exhibit a Hematopoietic Response [ Time Frame: 16 Weeks ]
   Hematopoietic response was defined as Hemoglobin (Hb) increment of 2.0 g/dL from baseline or achievement of Hb >= 11 g/dL (whichever occurs first) in the absence of red blood cell transfusions during the preceding 28 days during the treatment period.

Secondary Outcome Measures :

1. Percentage of Patients Maintaining an Average Hemoglobin Level Within the National Comprehensive Cancer Network (NCCN) Range (11-13 g/dL) Through Week 16, Once Achieving a Hemoglobin of ≥ 11 g/dL [ Time Frame: 16 Weeks ]
2. Incidence of Patients Receiving at Least One Red Blood Cell (RBC) Transfusions [ Time Frame: Week 1 to Week 16 ]
3. Mean Increment in Hemoglobin Level at Week 7 [ Time Frame: Baseline and 7 weeks ]
   Value at 7 weeks minus value at baseline.
4. Mean Increment in Hemoglobin Level at Week 16 [ Time Frame: Baseline and 16 weeks ]
   Value at 16 weeks minus value at baseline.
5. Time to Hematopoietic Response [ Time Frame: 16 weeks ]
   Hematopoietic response was defined as Hb increment of 2.0 g/dL from baseline or achievement of Hb >= 11 g/dL (whichever occurs first) in the absence of red blood cell transfusions during the preceding 28 days during the treatment period.
6. Time to First Red Blood Cell (RBC) Transfusions [ Time Frame: 16 weeks ]
7. Change From Baseline in Overall Quality of Life (QOL) Score as Measured by the Linear Analogue Self Assessment (LASA) [ Time Frame: Baseline and 16 weeks ]
   Overall QOL item score range: 0 (Worst) to 10 (Best), ordinal. Change: score at 16 weeks minus score at baseline.
8. Change From Baseline in Quality of Life (QOL) Score as Measured by Symptom Distress Scale (SDS) at End of Study [ Time Frame: Baseline and 16 weeks ]
   SDS Scale range: 0 (Worst), 100 (Best), ordinal. Change: score at 16 weeks minus score at baseline. A clinically significant result will be defined as a shift of 10 points on a 0-100 point transformed scale between the average QOL scores of the 3 variants of iron therapy.
9. Change From Baseline in Quality of Life (QOL) Score as Measured by Brief Fatigue Inventory(BFI) Fatigue Now Scale at End of Study [ Time Frame: Baseline and 16 weeks ]
   Fatigue Now Scale range: 0 (No Fatigue) to 10 (Worst), ordinal. Change: score at 16 weeks minus score at baseline.
10. Change From Baseline in Quality of Life (QOL) Score as Measured by The Functional Assessment of Cancer Therapy-Anemia (FACT-An) at End of Study [ Time Frame: Baseline and 16 weeks ]
    FACT-AN Scale range: 0 (Worst) to 100 (Best), ordinal. Change: score at 16 weeks minus score at baseline. A clinically significant result will be defined as a shift of 10 points on a 0-100 point transformed scale between the average QOL scores of the 3 variants of iron therapy.
11. C-reactive Protein (CRP) Level at Week 1, Week 7 and Week 16 [ Time Frame: 1 Week, 7 Weeks and 16 Weeks ]
12. Soluble Transferrin Receptor (sTfR)Level at Week 1, Week 7 and Week 16 [ Time Frame: 1 week, 7 weeks and 16 weeks ]
13. Ferritin Level at Baseline, Week 7 and Week 16 [ Time Frame: Baseline, 7 weeks and 16 weeks ]
14. Mean Corpuscular Volume (MCV) Level at Baseline, Week 7 and Week 16 [ Time Frame: Baseline, 7 weeks and 16 weeks ]
    MCV is a measure of the average red blood cell volume.
15. Transferrin Saturation at Baseline, Week 7 and Week 16 [ Time Frame: Baseline, 7 weeks and 16 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of a non-myeloid cancer (other than non-melanomatous skin cancer)
• Receiving or scheduled to receive chemotherapy (biological agents, such as small molecules/tyrosine kinase inhibitors and antibody-based therapies, are allowed)

• Has chemotherapy-related anemia (hemoglobin < 11 g/dL)

  • No anemia known to be secondary to gastrointestinal bleeding or hemolysis

  • No anemia known to be secondary to vitamin B12 or folic acid deficiency

    + Vitamin B12 and folic acid deficiency must be ruled out if the mean corpuscular volume (MCV) is > 100 fL

  • No anemia secondary to chemotherapy-induced myelodysplastic syndromes

• No primary hematologic disorder causing moderate to severe anemia (e.g., congenital dyserythropoietic anemia, homozygous hemoglobin S disease or compound heterozygous sickling states, or thalassemia major)

  - Carriers for these disease states are eligible

• No first-degree relative with primary hemochromatosis (unless the patient has undergone HFE genotyping and was found to have at least one wild-type allele, while the proband in the family demonstrated to have either the common C282Y or H63D mutation)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Ferritin > 20 mcg/L (i.e., not obviously iron deficient)
• ALT or AST < 5 times upper limit of normal
• Alert, mentally competent, and able to sign informed consent
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study treatment
• Willing or able to be randomized and undergo study treatment
• Willing or able to fill out quality-of-life forms
• No uncontrolled hypertension (i.e., systolic blood pressure [BP] ≥ 180 mm Hg or diastolic BP ≥ 100 mm Hg)
• No history of uncontrolled cardiac arrhythmias
• No pulmonary embolism or deep venous thrombosis within the past year (unless the patient is on anticoagulation therapy and planning to continue it during study participation)
• No known hypersensitivity to darbepoetin alfa, erythropoietin, mammalian cell-derived products, iron, or human albumin
• No seizures within the past 3 months
• No gastrointestinal conditions expected to cause significant impairment of oral iron, such as untreated celiac disease or amyloidosis involving the gut - Patients with celiac disease who are adhering to a gluten-free diet are eligible

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 3 months since prior darbepoetin alfa, epoetin alfa, or any investigational forms of erythropoietin (e.g., gene-activated erythropoietin or novel erythropoiesis-stimulating protein)
• More than 1 year since prior peripheral blood stem cell or bone marrow transplantation
• More than 2 weeks since prior red blood cell transfusions
• More than 14 days since prior major surgery
• No prior gastrectomy or resection of > 100 cm of small intestine
• Not planning to undergo stem cell or bone marrow transplantation within the next 6 months

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic in Arizona

Scottsdale, Arizona, United States

United States, Minnesota

Mayo Clinic

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

National Cancer Institute (NCI)

Investigators

• Study Chair: Charles L. Loprinzi, MD; Mayo Clinic
• Principal Investigator: Tom R. Fitch, M.D.; Mayo Clinic

More Information

• Responsible Party: Charles Lawrence Loprinzi, M.D., Mayo Clinic Cancer Center
• ClinicalTrials.gov Identifier: NCT00661999
• Other Study ID Numbers: CDR0000593480; P30CA015083 ( U.S. NIH Grant/Contract ); MC04CC ( Other Identifier: Mayo Clinic Cancer Center ); NCI-2009-01226 ( Registry Identifier: NCI-CTRP ); 1713-05 ( Other Identifier: Mayo Clinic IRB )
• First Posted: April 21, 2008
• Results First Posted: April 18, 2011
• Last Update Posted: May 17, 2011
• Last Verified: May 2011

Keywords provided by Mayo Clinic:

unspecified adult solid tumor, protocol specific; monoclonal gammopathy of undetermined significance; extramedullary plasmacytoma; isolated plasmacytoma of bone; refractory multiple myeloma; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma; primary systemic amyloidosis; Waldenstrom macroglobulinemia; post-transplant lymphoproliferative disorder; stage I adult T-cell leukemia/lymphoma; stage II adult T-cell leukemia/lymphoma; stage III adult T-cell leukemia/lymphoma; stage IV adult T-cell leukemia/lymphoma; recurrent adult T-cell leukemia/lymphoma; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphoma; stage I cutaneous T-cell non-Hodgkin lymphoma; stage II cutaneous T-cell non-Hodgkin lymphoma; stage III cutaneous T-cell non-Hodgkin lymphoma; stage IV cutaneous T-cell non-Hodgkin lymphoma; recurrent cutaneous T-cell non-Hodgkin lymphoma; stage I mycosis fungoides/Sezary syndrome; stage II mycosis fungoides/Sezary syndrome; stage III mycosis fungoides/Sezary syndrome; stage IV mycosis fungoides/Sezary syndrome; recurrent mycosis fungoides/Sezary syndrome; stage I adult Hodgkin lymphoma; stage II adult Hodgkin lymphoma

Additional relevant MeSH terms:

Lymphoma; Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Precancerous Conditions; Anemia; Lymphoproliferative Disorders; Neoplasms by Histologic Type; Neoplasms; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Darbepoetin alfa; Ferric gluconate; Hematinics