Breast Cancer, Folic Acid Deficiency, Ovarian Cancer
Conditions
Keywords
ovarian cancer, breast cancer, olaparib, folic acid deficiency
Brief summary
This is a study investigating folate deficiency (lack of folic acid in the blood) in patients who take the drug olaparib to treat their advanced ovarian or breast cancer.
Detailed description
This is a study investigating folate deficiency (lack of folic acid in the blood) in patients who take the drug olaparib to treat their advanced ovarian or breast cancer. The primary goal of this study is to determine the frequency and timing of folate deficiency, and to learn more about whether giving folic acid supplementation (vitamin) will help delay or avoid deficiency in these patients. Deficiency can cause doctors to reduce or stop treatment with olaparib. In this case, patients are not getting the best treatment for their cancer due to the unwanted side effect.
Interventions
Folic Acid 1 mg by mouth daily
Sponsors
Rush University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide signed informed consent * Female, post-menopausal, ≥18 years of age inclusive, at the time of signing the consent form * Individuals who have ovarian cancer or breast cancer who are recommended to start olaparib * Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below: * Haemoglobin ≥ 9 g/dL with no blood transfusion in the past 28 days * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Platelet count ≥ 100 x 109/L * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be ≤ 5x ULN * Patients must have creatinine clearance estimated of ≥51 mL/min * Eastern Cooperative Oncology Group (ECOG) performance status 0-1). * Patients must have a life expectancy ≥ 16 weeks. * At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT and is suitable for repeated assessment.
Exclusion criteria
* Patients with folic acid deficiency, defined as folate \<7 ng/mL, or those taking folic acid supplementation within 30 days of olaparib initiation. * Other malignancy unless curatively treated with no evidence of disease for ≥5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma. Patients with a history of localised triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease * Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome. * Persistent toxicities (\>Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia. * Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML. * Patients with symptomatic uncontrolled brain metastases. * Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. * Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication. * Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). * Patients with known active hepatitis (i.e. Hepatitis B or C). * Any previous treatment with PARP inhibitor, including Olaparib. * Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment * Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. * Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. * Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. * Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT). * Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable). * Participation in another clinical study with an investigational product administered in the last 1 month * Patients with a known hypersensitivity to olaparib or any of the excipients of the product. * Patients with a known hypersensitivity to folic acid or any of the excipients of the product. * Involvement in the planning and/or conduct of the study * Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements * Previous enrollment in the present study * Breast feeding women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Have Developed Folate Deficiency (Serum Folate Level < 7 ng/ml) on Olaparib | Serum folate levels were measured in each enrolled subject: at baseline, then every 2 weeks X 3 months, then monthly X 9 months. Accrual occurred over a 2-year period. | The number of patients with ovarian and breast cancers who were treated with olaparib and developed folate deficiency was counted. |
| Timing of Folate Deficiency Development | From the beginning of olaparib treatment until the development of folate deficiency | The number of weeks between the beginning of olaparib treatment and the development of folate deficiency |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants Who Developed Decreased Hemoglobin by ≥ 1 g/dl Relative to Baseline | Hemoglobin levels were measured in each enrolled subject: at baseline, then every 2 weeks X 3 months, then monthly X 9 months. Accrual occurred over a 2-year period. | To evaluate the effect of olaparib on hemoglobin level in both arms of the study as compared to baseline before the beginning of the olaparib treatment |
| Serum Folate | Serum folate levels were measured in each enrolled subject: at baseline, then every 2 weeks X 3 months, then monthly X 9 months. Accrual occurred over a 2-year period. | To evaluate the effect of folic acid supplementation on serum folate levels as compared to the no Folate supplementation arm. Serum folate was measured every 2 weeks for the first 3 months, and then monthly for 9 months during olaparib therapy. |
| Number of Participants Requiring Blood Transfusions | Over 12 months while on olaparib therapy. | The number of patients requiring blood transfusions during olaparib treatment was counted. |
| Number of Participants Requiring Olaparib Dose Interruptions | Over 12 months while on olaparib therapy. | The number of subjects requiring interruptions in olaparib treatment for any reason was counted. |
| Number of Participants Requiring Olaparib Dose Reductions for Any Reason | Over 12 months while on olaparib therapy. | The number of participants requiring olaparib dose reductions for any reason was counted. |
| Number of Participants Requiring Olaparib Discontinuation | Over 12 months while on olaparib therapy | The number of subjects who had their olaparib treatment discontinued was counted. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORLydia Usha, MD
Rush University Medical Center
Participant flow
Recruitment details
The protocol started in August 2020 and completed in August 2022. Patients were recruited from the Gynecologic Oncology and Breast Oncology clinics at a major medical center.
Pre-assignment details
Patients who were planned to receive the PARP inhibitor, Olaparib for the treatment for Ovarian or Breast cancer were eligible for the study. After obtaining consent, screening activities included baseline blood work and physical exam. One of the ten subjects was excluded as it was revealed that she had received prior PARP inhibitor treatment on a blinded trial.
Participants by arm
| Arm | Count |
|---|---|
| Folic Acid Supplementation Group Folic Acid supplement 1 mg by mouth daily
Folic Acid Tablet: Folic Acid 1 mg by mouth daily | 2 |
| No Supplementation No Folate supplementation | 7 |
| Total | 9 |
Baseline characteristics
| Characteristic | Folic Acid Supplementation Group | Total | No Supplementation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 5 Participants | 3 Participants |
| Age, Continuous | 49 years | 64 years | 66 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 9 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Folate levels at baseline | 10.5 ng/mL | 14.6 ng/mL | 18.6 ng/mL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants |
| Region of Enrollment United States | 2 participants | 9 participants | 7 participants |
| Sex: Female, Male Female | 2 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 2 / 7 |
| other Total, other adverse events | 0 / 2 | 2 / 7 |
| serious Total, serious adverse events | 0 / 2 | 0 / 7 |
Outcome results
Primary
Number of Participants Who Have Developed Folate Deficiency (Serum Folate Level < 7 ng/ml) on Olaparib
The number of patients with ovarian and breast cancers who were treated with olaparib and developed folate deficiency was counted.
Time frame: Serum folate levels were measured in each enrolled subject: at baseline, then every 2 weeks X 3 months, then monthly X 9 months. Accrual occurred over a 2-year period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid Supplementation Arm | Number of Participants Who Have Developed Folate Deficiency (Serum Folate Level < 7 ng/ml) on Olaparib | 2 Participants |
| No Supplementation | Number of Participants Who Have Developed Folate Deficiency (Serum Folate Level < 7 ng/ml) on Olaparib | 6 Participants |
Primary
Timing of Folate Deficiency Development
The number of weeks between the beginning of olaparib treatment and the development of folate deficiency
Time frame: From the beginning of olaparib treatment until the development of folate deficiency
Population: Only 6 subjects in the no folate supplementation arm developed folate deficiency.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Folic Acid Supplementation Arm | Timing of Folate Deficiency Development | 4 weeks |
| No Supplementation | Timing of Folate Deficiency Development | 3.4 weeks |
Secondary
Number of Participants Requiring Blood Transfusions
The number of patients requiring blood transfusions during olaparib treatment was counted.
Time frame: Over 12 months while on olaparib therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid Supplementation Arm | Number of Participants Requiring Blood Transfusions | 0 Participants |
| No Supplementation | Number of Participants Requiring Blood Transfusions | 0 Participants |
Secondary
Number of Participants Requiring Olaparib Discontinuation
The number of subjects who had their olaparib treatment discontinued was counted.
Time frame: Over 12 months while on olaparib therapy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid Supplementation Arm | Number of Participants Requiring Olaparib Discontinuation | 0 Participants |
| No Supplementation | Number of Participants Requiring Olaparib Discontinuation | 1 Participants |
Secondary
Number of Participants Requiring Olaparib Dose Interruptions
The number of subjects requiring interruptions in olaparib treatment for any reason was counted.
Time frame: Over 12 months while on olaparib therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid Supplementation Arm | Number of Participants Requiring Olaparib Dose Interruptions | 1 Participants |
| No Supplementation | Number of Participants Requiring Olaparib Dose Interruptions | 0 Participants |
Secondary
Number of Participants Requiring Olaparib Dose Reductions for Any Reason
The number of participants requiring olaparib dose reductions for any reason was counted.
Time frame: Over 12 months while on olaparib therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid Supplementation Arm | Number of Participants Requiring Olaparib Dose Reductions for Any Reason | 0 Participants |
| No Supplementation | Number of Participants Requiring Olaparib Dose Reductions for Any Reason | 2 Participants |
Secondary
Serum Folate
To evaluate the effect of folic acid supplementation on serum folate levels as compared to the no Folate supplementation arm. Serum folate was measured every 2 weeks for the first 3 months, and then monthly for 9 months during olaparib therapy.
Time frame: Serum folate levels were measured in each enrolled subject: at baseline, then every 2 weeks X 3 months, then monthly X 9 months. Accrual occurred over a 2-year period.
Population: We calculated the average folate level for each data point in each arm of the study.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Folic Acid Supplementation Arm | Serum Folate | 14 weeks | 24.0 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 5 month | 18.5 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 6 month | 11.2 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 7 month | 10.5 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 8 month | 13.6 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 9 month | 9.1 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 10 month | 11.6 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 11 month | 5.9 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 12 month | 12.4 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 30 day follow up | 6.0 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 2 week | 5.5 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 4 week | 6.5 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 6 week | 8.4 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 8 week | 3.6 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 10 week | 15.9 ng/ml |
| Folic Acid Supplementation Arm | Serum Folate | 12 week | 24.1 ng/ml |
| No Supplementation | Serum Folate | 12 week | 6.1 ng/ml |
| No Supplementation | Serum Folate | 14 weeks | 10.5 ng/ml |
| No Supplementation | Serum Folate | 12 month | 9.3 ng/ml |
| No Supplementation | Serum Folate | 5 month | 9.5 ng/ml |
| No Supplementation | Serum Folate | 6 week | 7.8 ng/ml |
| No Supplementation | Serum Folate | 6 month | 5.6 ng/ml |
| No Supplementation | Serum Folate | 30 day follow up | 9.3 ng/ml |
| No Supplementation | Serum Folate | 7 month | 6.8 ng/ml |
| No Supplementation | Serum Folate | 10 week | 8.1 ng/ml |
| No Supplementation | Serum Folate | 8 month | 5.8 ng/ml |
| No Supplementation | Serum Folate | 2 week | 7.7 ng/ml |
| No Supplementation | Serum Folate | 9 month | 8.2 ng/ml |
| No Supplementation | Serum Folate | 8 week | 4.0 ng/ml |
| No Supplementation | Serum Folate | 10 month | 7.5 ng/ml |
| No Supplementation | Serum Folate | 4 week | 4.6 ng/ml |
| No Supplementation | Serum Folate | 11 month | 6.8 ng/ml |
Secondary
The Number of Participants Who Developed Decreased Hemoglobin by ≥ 1 g/dl Relative to Baseline
To evaluate the effect of olaparib on hemoglobin level in both arms of the study as compared to baseline before the beginning of the olaparib treatment
Time frame: Hemoglobin levels were measured in each enrolled subject: at baseline, then every 2 weeks X 3 months, then monthly X 9 months. Accrual occurred over a 2-year period.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Folic Acid Supplementation Arm | The Number of Participants Who Developed Decreased Hemoglobin by ≥ 1 g/dl Relative to Baseline | 1 Participants |
| No Supplementation | The Number of Participants Who Developed Decreased Hemoglobin by ≥ 1 g/dl Relative to Baseline | 2 Participants |