IMRT + Chemotherapy + Stem Cell Transplant for Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: City of Hope Medical Center

Disqualifiers: Prior radiation, Previous transplant, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

51 Participants Needed

Trial Summary

What is the purpose of this trial?

RATIONALE: Giving intensity modulated radiation therapy (IMRT) and chemotherapy, such as etoposide and cyclophosphamide, before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving IMRT together with chemotherapy before transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects and best dose of intensity-modulated radiation therapy (IMRT) when given together with etoposide and cyclophosphamide followed by donor stem cell transplant and to see how well they work in treating patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment IMRT + Chemotherapy + Stem Cell Transplant for Leukemia?

Research shows that adding medium-dose etoposide (a chemotherapy drug) to the standard cyclophosphamide and total body irradiation regimen in allogeneic stem cell transplantation can significantly reduce relapse and improve leukemia-free survival in high-risk acute lymphoblastic leukemia patients. ^{1 2 3 4 5}

Is the treatment of IMRT + Chemotherapy + Stem Cell Transplant for Leukemia generally safe in humans?

Etoposide (VP-16), a chemotherapy drug used in this treatment, can cause hypersensitivity reactions like rashes and low blood pressure, but these are usually mild and manageable. High doses of etoposide can lead to reversible mouth sores, and there is a risk of developing secondary leukemia, although this is rare. Overall, the treatment has been used safely in humans, but it does carry some risks. ^{1 6 7 8 9}

How is the treatment with IMRT, chemotherapy, and stem cell transplant for leukemia different from other treatments?

This treatment is unique because it combines intensity-modulated radiation therapy (IMRT), which precisely targets cancer cells while sparing healthy tissue, with chemotherapy drugs like Cyclophosphamide and Etoposide, and a stem cell transplant to potentially improve outcomes for leukemia patients. This combination aims to enhance tumor control and reduce side effects compared to traditional methods. ^{10 11 12 13 14}

Research Team

Anthony S. Stein, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) who have not responded to initial treatments. They must have a suitable sibling or matched unrelated donor for stem cell transplant, good kidney and liver function, acceptable heart health, and no previous bone marrow transplants. Pregnant individuals cannot participate.

Inclusion Criteria

Patients must have a serum creatinine of less than or equal to 1.2 or creatinine clearance > 80 ml/min

Patients with acute lymphocytic leukemia or acute myelogenous leukemia who are not in first or second remission (i.e., after failing remission induction therapy or in relapse or beyond second remission)

All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical sibling who is willing to donate bone marrow or primed blood stem cells or a 10/10 allele matched unrelated donor; a single allele mismatch at A, B, C, DR, or DQ and a KIR mismatch at C will be allowed; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques

Exclusion Criteria

You have had a previous bone marrow transplant and experienced a relapse.

Prior radiation therapy that would exclude the use of total-body irradiation

Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50%

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Patients undergo IMRT using helical tomotherapy and receive etoposide and cyclophosphamide intravenously as a preparative regimen for transplantation

7-10 days

Daily visits for radiation and chemotherapy administration

Transplantation

Patients undergo allogeneic peripheral blood stem cell or bone marrow transplantation

1-2 days

Inpatient procedure

Follow-up

Participants are monitored for safety, effectiveness, and transplant-related outcomes

2 years

Periodic visits for up to 2 years

Treatment Details

Interventions

• Allogeneic Bone Marrow Transplantation
• Allogeneic Hematopoietic Stem Cell Transplantation
• Cyclophosphamide
• Etoposide
• Intensity-Modulated Radiation Therapy
• Peripheral Blood Stem Cell Transplantation

Trial Overview The study tests whether using intensity-modulated radiation therapy (IMRT) with chemotherapy drugs etoposide and cyclophosphamide before a stem cell transplant from a donor can effectively treat relapsed/refractory ALL or AML without causing the immune system to reject the new cells.

Participant Groups

Group I: Level 9: 2000cGy limited dose to liver, porta-hepatic, brain 1200cGy Experimental Treatment 7 Interventions

200cGy BID Day 1-5. Total dose 2000Gy.

Group II: Level 8: 1900cGy limited dose to liver, porta-hepatic, brain 1200cGy Experimental Treatment 7 Interventions

190cGy BID Day 1-5. Total dose 1900Gy.

Group III: Level 7: 1800cGy limited dose to liver, porta-hepatic, brain 1200cGy Experimental Treatment 7 Interventions

180cGy BID Day 1-5. Total dose 1800Gy.

Group IV: Level 6: 1700cGy limited dose to liver, porta-hepatic, brain 1200cGy Experimental Treatment 7 Interventions

170cGy BID Day 1-5. Total dose 1700Gy.

Group V: Level 5: 1600cGy limited dose to liver, porta-hepatic, brain 1200cGy Experimental Treatment 7 Interventions

160cGy BID Day 1-5. Total dose 1600Gy.

Group VI: Level 4: 1500cGy limited dose to liver, brain 1200cGy Experimental Treatment 7 Interventions

150cGy BID Day 1-5. Total dose 1500Gy.

Group VII: Level 3: 1500cGy limited dose to ribs, sternum, liver, brain 1200cGy Experimental Treatment 7 Interventions

150cGy BID Day 1-5. Total dose 1500Gy.

Group VIII: Level 2: 1350cGy Experimental Treatment 7 Interventions

150cGy BID Day 1-4 then 150 cGy QD Day 5. Total dose 1350cGy.

Group IX: Level 1: 1200cGy Experimental Treatment 7 Interventions

150cGy BID x Days 1-4. Total dose 1200cGy.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

A low-dose oral combination of estramustine phosphate (EMP) and etoposide (VP16) was well-tolerated in 56 hormone-refractory prostate cancer patients, showing a significant advantage in time to treatment interruption due to toxicity compared to higher doses.

Patients receiving the low-dose combination experienced a trend towards greater PSA reduction (41.4% vs. 15%) and improved performance status and pain, indicating its potential as a safe outpatient treatment option for those unfit for intravenous chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral chemotherapy in hormone-refractory prostate carcinoma patients unwilling to be admitted to hospital. Serretta, V., Altieri, V., Morgia, G., et al.[2013]

In a Phase II study involving 20 patients with hormone-refractory prostate carcinoma, the oral combination of cyclophosphamide and etoposide showed a 35% objective response rate, with one complete response and six partial responses based on PSA levels.

The treatment was well tolerated, with minimal toxicities, and resulted in improved performance status for 26% of patients and relief of bone pain in 71%, indicating its potential efficacy in managing symptoms and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Maulard-Durdux, C., Dufour, B., Hennequin, C., et al.[2019]

Intensity modulated radiation therapy (IMRT) has shown promising results in treating various tumors, including prostate, head and neck, and brain cancers, based on a retrospective review of 185 patients.

IMRT not only effectively targets tumors while minimizing damage to surrounding healthy tissues, but it also allows for dose escalation, which can improve tumor control and reduce treatment-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity modulated radiotherapy (IMRT) decreases treatment-related morbidity and potentially enhances tumor control. Teh, BS., Mai, WY., Grant, WH., et al.[2019]

The use of intensity-modulated radiation therapy (IMRT) among U.S. radiation oncologists has significantly increased from 32% in 2002 to 73.2% in 2004, indicating a growing acceptance of this treatment method.

IMRT is primarily adopted for its ability to deliver higher radiation doses while sparing normal tissues, with 81% of users citing this as a key benefit, highlighting the need for standardized guidelines to evaluate its risks and benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy use in the U.S., 2004. Mell, LK., Mehrotra, AK., Mundt, AJ.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Oral chemotherapy in hormone-refractory prostate carcinoma patients unwilling to be admitted to hospital. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Improved prognosis with additional medium-dose VP16 to CY/TBI in allogeneic transplantation for high risk ALL in adults. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Etoposide in leukemia, lymphoma and bone marrow transplantation. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Etoposide in the treatment of leukemias. [2018]

6. Japan pubmed.ncbi.nlm.nih.gov

[Dose escalation study of high dose etoposide in autologous hematopoietic stem cell transplantation]. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia. [2019]

8. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of high-dose cytosine arabinoside and etoposide in patients with advanced malignancies. [2019]

9. United States pubmed.ncbi.nlm.nih.gov

Secondary acute myelogenous leukemia following safe exposure to etoposide. [2017]

10. Italy pubmed.ncbi.nlm.nih.gov

Recommendations for treatment with IMRT for prostate and head-neck cancer. Axencia de Avaliación de Tecnoloxías Sanitarias de Galicia. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Treatment planning comparison of IMPT, VMAT and 4π radiotherapy for prostate cases. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Intensity modulated radiotherapy (IMRT) decreases treatment-related morbidity and potentially enhances tumor control. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Intensity-modulated radiation therapy use in the U.S., 2004. [2018]

14. United States pubmed.ncbi.nlm.nih.gov

Volumetric arc therapy and intensity-modulated radiotherapy for primary prostate radiotherapy with simultaneous integrated boost to intraprostatic lesion with 6 and 18 MV: a planning comparison study. [2022]