Gemcitabine Plus Ascorbate for Sarcoma in Adults

• Sponsor: Mohammed Milhem, MBBS (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03468075
• Collaborator: University of Iowa Adolescent and Young Adult (AYA) Cancer Program (Other), St. Baldrick's Foundation (Other), University of Iowa (Other)
• Enrollment: 10
• Location: 1
• Arm: 1
• Actual Duration (Months): 27.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will enroll patients who have a diagnosis of locally advanced, unresectable or metastatic soft tissue or bone sarcoma (except gastrointestinal stromal tumors and Kaposi's sarcoma) from any site.

Condition or Disease	Intervention/Treatment	Phase
Sarcoma; Soft Tissue Sarcoma; Unresectable Soft Tissue Sarcoma; Metastatic Bone Tumor; Bone Sarcoma	Drug: Ascorbate; Drug: Gemcitabine	Phase 2

Detailed Description

This study will enroll male and female patients 18 years old or older who have a diagnosis of locally advanced, unresectable or metastatic soft tissue or bone sarcoma (except GIST and Kaposi's) from any site. A minimum of 1 prior chemotherapy regimen, including adjuvant and neo-adjuvant therapy for the treatment of sarcoma, must have been given. Patients eligible for an anthracycline should have received a prior anthracycline containing regimen. Patients who decline or are not eligible for anthracycline treatment may be considered for this protocol as a first line treatment. Patients with a diagnosis of liposarcoma should also have received eribulin.

During screening, subjects will receive a test dose (15g) of ascorbate. If the test dose results in any toxicity >/= CTCAE grade 3 or a significant medical event in the opinion of the principal investigator, the patient will be considered a screen failure.

Subjects who pass screening will then receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for at least 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Treatment will be terminated with progression of disease. Disease will be assessed by CT of the chest, abdomen and pelvis or MRI of the lesion every 2 cycles for progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Gemcitabine Plus High-Dose Ascorbate in Locally Advanced Unresectable or Metastatic Soft Tissue and Bone Sarcomas in Adults
• Actual Study Start Date: Jul 11, 2018
• Actual Primary Completion Date: Apr 16, 2019
• Actual Study Completion Date: Oct 19, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Gemcitabine + High-Dose Ascorbate Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator.

Drug: Ascorbate; Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle; Other Names: Ascorbic Acid Vitamin C Pharmacological ascorbate ; Drug: Gemcitabine; Administered on Days 1, 8 and 15, after the infusion of ascorbate; Other Names: Gemzar

Outcome Measures

Primary Outcome Measures

1. Tumor Response [Every 2 months for first 6 months, then every 3 months up to 2 years post treatment]

   From first day of treatment to documented disease progression as described by RECIST 1.1 criteria. Results are provided in nominal categories (CR, PR, SD, PD) as per RECIST.

Secondary Outcome Measures

1. Progression Free Survival [Every 2 months for first 6 months, then every 3 months up to 2 years post treatment]

   Time from start of therapy (day 1, cycle 1) to documented disease progression or death due to any cause. Progression will be defined using the RECIST 1.1 guidelines. Results are provided in nominal categories (CR, PR, SD, PD) as per RECIST.

2. Overall Survival [Every 2 months for first 6 months, then every 3 months up to 2 years post treatment]

   Time from start of therapy (day 1, cycle 1) to death.

3. Incidence of Adverse Events (AE) Per CTCAE 4.03 [Up to 30 days after completion of study treatment]

   Categorize and quantify adverse events from start of therapy (day 1, cycle 1) to end of study per (CTCAE) version 4.03.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients aged ≥ 18 years old

2. ECOG Performance Status of ≤ 2

3. Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed

• Patients must meet the following laboratory criteria:

• Hematology:

• Neutrophil count of >1500/mm3

• Platelet count of > 100,000/mm3L

• Hemoglobin ≥ 9 g/dL (transfusion to meet eligibility allowed)

• Biochemistry:

• AST/SGOT and ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to disease involvement

• Alkaline phosphatase < 5 x ULN

• Serum bilirubin ≤ 1.5 x ULN

• Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min

• Total serum calcium >/= LLN or if calcium is below LLN then corrected calcium for serum albumin should be >/= LLN

• Serum potassium ≥ LLN

• Serum sodium ≥ LLN

• Serum albumin ≥ LLN or 3g/dl

1. Tolerate a 15g ascorbate infusion (screening dose)

2. Baseline MUGA or ECHO done only in subjects with prior doxorubicin exposure. The test must demonstrate LVEF ≥ the lower limit of the institutional normal.

3. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of study treatment and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration

4. Any patient with the diagnosis of locally advanced, unresectable or metastatic soft tissue or bone sarcoma (except GIST and Kaposi's) from any site. A minimum of 1 prior chemotherapy regimen, including adjuvant and neo-adjuvant therapy for the treatment of sarcoma. Patients eligible for an anthracycline should have received a prior anthracycline containing regimen. Patients who decline or are not eligible for anthracycline treatment may be considered for this protocol as a first line treatment. Patients with a diagnosis of liposarcoma should also have received eribulin if they received anthracycline-based therapy prior to eribulin. Patients with a diagnosis of myxoid liposarcoma should have received trabectedin. Patients with angiosarcoma should have received either taxol or docetaxel. Patients must have measurable disease defined as at least 1 lesion ≥ 1cm in the greatest dimension.

5. Patients with metastatic bone sarcomas who have failed all available therapies that have demonstrated clinical benefit. Available therapies include but not limited to methotrexate, adriamycin and cisplatin for osteosarcoma and vincristine, adriamycin and Cytoxan, ifosfamide, etoposide (VAC/IE)for Ewing's sarcoma.

6. Previous exposure to Gemcitabine will only be allowed if there is no residual toxicity from previous treatments. Toxicity must be graded as 0 or 1 prior to study.

7. Patients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with locally advanced unresectable or metastatic disease.

Exclusion Criteria:

1. G6PD (glucose-6-phosphate dehydrogenase) deficiency

2. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix E)

3. History of myocardial infarction or unstable angina within 6 months prior to Day 1

4. History of stroke or transient ischemic attack within 6 months prior to Day 1

5. Known CNS disease, except for treated brain metastasis: Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded

6. Actively receiving insulin or requiring fingerstick glucose monitoring at time of ascorbate infusion (unless an exception is granted by the IND sponsor, medical monitor, and the PI).

7. Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1

8. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)

9. Pregnancy (positive pregnancy test) or lactation. Use of effective means of contraception (men and women) in subjects of child-bearing potential

10. Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs.

11. Other concurrent severe and/or uncontrolled medical conditions

12. Patients who have received chemotherapy or any investigational drug < 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.

13. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study.

14. Concomitant use of any anti-cancer therapy or radiation therapy. Palliative radiation therapy to non-target lesions is permitted.

15. Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment. One of these methods must be a condom.

16. Patients with a history of another primary malignancy within 2 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin

17. Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required. High-dose ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs.

18. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent.

19. Patients with GIST tumors and Kaposi's Sarcoma are excluded.

20. Patients with history of more than one symptomatic oxalate stone in the last 6 months or visible stone in the kidney or ureter on screening CT scan.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242

Sponsors and Collaborators

• Mohammed Milhem, MBBS
• University of Iowa Adolescent and Young Adult (AYA) Cancer Program
• St. Baldrick's Foundation
• University of Iowa

Investigators

• Principal Investigator: Varun Monga, MD, University of Iowa

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 13, 2019
• Informed Consent Form - Sep 1, 2018

More Information

Publications

None provided.

• Responsible Party: Varun Monga, MD, Assistant Clinical Professor, University of Iowa
• ClinicalTrials.gov Identifier: NCT03468075
• Other Study ID Numbers: 201802800 (Phase II)
• First Posted: Mar 16, 2018
• Last Update Posted: Dec 10, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Varun Monga, MD, Assistant Clinical Professor, University of Iowa: Sarcoma; Soft tissue; Ascorbate
• Additional relevant MeSH terms: Sarcoma; Osteosarcoma; Ascorbic Acid; Gemcitabine

Study Results

Participant Flow

Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	4 40%
>=65 years	6 60%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	68
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%
Not Hispanic or Latino	9 90%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 10%
White	8 80%
More than one race	0 0%
Unknown or Not Reported	1 10%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Tumor Response
Description	From first day of treatment to documented disease progression as described by RECIST 1.1 criteria. Results are provided in nominal categories (CR, PR, SD, PD) as per RECIST.
Time Frame	Every 2 months for first 6 months, then every 3 months up to 2 years post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
Measure Participants	10
PD	8 80%
SD	1 10%
PR	1 10%

2. Secondary Outcome

Title	Progression Free Survival
Description	Time from start of therapy (day 1, cycle 1) to documented disease progression or death due to any cause. Progression will be defined using the RECIST 1.1 guidelines. Results are provided in nominal categories (CR, PR, SD, PD) as per RECIST.
Time Frame	Every 2 months for first 6 months, then every 3 months up to 2 years post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
Measure Participants	10
2 months	7 70%
3 months	1 10%
6 months	1 10%
9 months	1 10%

3. Secondary Outcome

Title	Overall Survival
Description	Time from start of therapy (day 1, cycle 1) to death.
Time Frame	Every 2 months for first 6 months, then every 3 months up to 2 years post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
Measure Participants	10
Alive	5 50%
Dead	5 50%

4. Secondary Outcome

Title	Incidence of Adverse Events (AE) Per CTCAE 4.03
Description	Categorize and quantify adverse events from start of therapy (day 1, cycle 1) to end of study per (CTCAE) version 4.03.
Time Frame	Up to 30 days after completion of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
Measure Participants	10
Blood and lymphatic system disorders	4
Gastrointestinal disorders	7
Infections and infestations	1
Investigations	43
Metabolism and nutrition disorders	2
Musculoskeletal and connective tissue disorders	1
Psychiatric disorders	1
Renal and urinary disorders	1
Respiratory, thoracic and mediastinal disorders	11
Skin and subcutaneous tissue disorders	3
Vascular disorders	2
General disorders and administration site conditions	7

Adverse Events

Time Frame	AEs were collected up to 30 days after completion of study treatment, up to 7 months
Adverse Event Reporting Description	Information about all adverse events, whether volunteered by the subject, discovered by investigator questioning, or detected through physical examination, laboratory test or other means, were collected and recorded and followed as appropriate. Adverse events were followed for 30 days post last dose of drug.
Arm/Group Title	Gemcitabine + High-Dose Ascorbate
Arm/Group Description	Subjects will receive ascorbate, 75g, on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Gemcitabine will be administered on Days 1, 8 and 15, after the infusion of ascorbate. Concomitant treatment will continue for 6 cycles. Patients whose disease has not progressed while receiving gemcitabine and ascorbate and who are tolerating therapy may continue either single agent gemcitabine or concomitant treatment beyond 6 cycles at the discretion of the investigator. Ascorbate: Following 15g test dose, 75g administered on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle Gemcitabine: Administered on Days 1, 8 and 15, after the infusion of ascorbate
All Cause Mortality
	Gemcitabine + High-Dose Ascorbate
	Affected / at Risk (%)	# Events
Total	6/10 (60%)
Serious Adverse Events
	Gemcitabine + High-Dose Ascorbate
	Affected / at Risk (%)	# Events
Total	2/10 (20%)
Gastrointestinal disorders
Abdominal pain	1/10 (10%)	1
General disorders
Fever	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Gemcitabine + High-Dose Ascorbate
	Affected / at Risk (%)	# Events
Total	9/10 (90%)
Blood and lymphatic system disorders
Anemia	2/10 (20%)	4
Gastrointestinal disorders
Abdominal pain	1/10 (10%)	1
Ascites	1/10 (10%)	1
Constipation	2/10 (20%)	2
Nausea	2/10 (20%)	2
Vomiting	1/10 (10%)	1
General disorders
Chills	1/10 (10%)	1
Edema limbs	1/10 (10%)	1
Fatigue	1/10 (10%)	1
Fever	2/10 (20%)	3
Pain	1/10 (10%)	1
Infections and infestations
Upper respiratory infection	1/10 (10%)	1
Investigations
Alanine aminotransferase increased	2/10 (20%)	2
Aspartate aminotransferase increased	1/10 (10%)	1
Blood bilirubin increased	1/10 (10%)	1
GGT increased	1/10 (10%)	2
Neutrophil count decreased	6/10 (60%)	9
Platelet count decreased	6/10 (60%)	26
Weight loss	1/10 (10%)	2
Metabolism and nutrition disorders
Anorexia	1/10 (10%)	1
Metabolism and nutrition disorders - Other, specify	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/10 (10%)	1
Psychiatric disorders
Insomnia	1/10 (10%)	1
Renal and urinary disorders
Hematuria	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/10 (20%)	2
Dyspnea	2/10 (20%)	3
Hypoxia	1/10 (10%)	1
Pleural effusion	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	3/10 (30%)	4
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/10 (10%)	2
Skin and subcutaneous tissue disorders - Other, specify	1/10 (10%)	1
Vascular disorders
Hypertension	2/10 (20%)	2

Limitations/Caveats

Study terminated early. Ten patients were enrolled in the first stage, and per protocol the study was terminated following interim analysis when 1 or fewer participants had a tumor response.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.