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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of treatments for individuals with specific types of leukemia (acute lymphoblastic leukemia or acute myeloid leukemia) that have not responded well to other treatments. It combines precise radiation therapy (Intensity-Modulated Radiation Therapy, or IMRT), chemotherapy, and a donor stem cell transplant to eliminate cancer cells and help the body accept new, healthy cells. The trial aims to determine the optimal radiation dose and evaluate the effectiveness of this combination. Individuals who have struggled to achieve remission and have a willing donor match may be suitable candidates for this study. As a Phase 1, Phase 2 trial, the study seeks to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of treatments in this clinical trial has mixed safety results based on previous studies.

Intensity-modulated radiation therapy (IMRT) proves effective and does not significantly increase the risk of leukemia compared to other radiation therapies, suggesting it might be a safer choice for radiation treatment.

Cyclophosphamide, a common chemotherapy drug for various cancers, works well but can cause serious side effects like reduced bone marrow activity, leading to fewer blood cells, and possibly other long-term risks such as infertility or new cancers.

Etoposide, another chemotherapy drug, effectively treats cancers but carries a risk of causing secondary acute myelogenous leukemia, even at safe doses. While it can help fight the original cancer, it might lead to another cancer later on.

Overall, the treatments combined in this trial have demonstrated effectiveness in past studies but come with risks that require careful management. Participants should be aware of these potential side effects and discuss them with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for leukemia because it uniquely integrates Intensity-Modulated Radiation Therapy (IMRT) with chemotherapy and stem cell transplant. Unlike standard treatments that might use traditional radiation, IMRT allows for more precise targeting, minimizing damage to surrounding healthy tissues. Additionally, the regimen varies radiation doses across different levels, which could optimize effectiveness while reducing side effects. This innovative approach aims to enhance the overall treatment outcomes for leukemia patients, offering hope for more effective and safer therapy options.

What evidence suggests that this trial's treatments could be effective for leukemia?

Research has shown that intensity-modulated radiation therapy (IMRT), one of the treatments in this trial, leads to fewer long-term side effects than traditional radiation methods, making it a promising option for leukemia patients. Cyclophosphamide, another treatment option in this trial, works well with other cancer drugs and has shown high success rates in treating acute leukemia. Etoposide, also part of this trial, has proven effective, with some patients achieving complete recovery. This trial will explore using IMRT alongside these chemotherapy drugs to help stop cancer growth and prepare the body for a stem cell transplant. ^{2 6 7 8 9}

Who Is on the Research Team?

Anthony S. Stein, MD

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9176122/

Combination of cyclophosphamide and cytarabine as ... With one course of induction chemotherapy, the overall response rate and the complete remission rate (CR) was 82.5% (33/40) and 77.5% (31/40), respectively. The ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4734089/

Cyclophosphamide combined with mitoxantrone and ... The overall survival rate and disease-free survival rate were 72.1 and 59.7% at 1 year, 42.9 and 47.1% at 3 years, and 36.7 and 43.0% at 5 years, respectively.

3. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/pdfdirect/10.1002/1097-0142%28196611%2919%3A11%3C1551%3A%3AAID-CNCR2820191116%3E3.0.CO%3B2-Z

Cyclophosphamide therapy in acute leukemia of childhood Cyclo- phosphamide, administered orally, is effective for the treatment of acute leukemia for children in early relapse but is not effective in patients in ...

4. cancerindex.org cancerindex.org/Cyclophosphamide

Cyclophosphamide RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2020/212501s000lbl.pdf

cyclophosphamide injection - accessdata.fda.gov Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs. 2.

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK553087/

Cyclophosphamide - StatPearls - NCBI Bookshelf - NIH Cyclophosphamide is a medication primarily used in the management and treatment of neoplasms, including multiple myeloma, sarcoma, and breast cancer.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2019/203856s003lbl.pdf

cyclophosphamide capsules - accessdata.fda.gov Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data].

8. go.drugbank.com go.drugbank.com/drugs/DB00531

Cyclophosphamide: Uses, Interactions, Mechanism of Action Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. Modality: Small Molecule; Groups: Approved, Investigational; Structure. 3D.

9. mayoclinic.org mayoclinic.org/drugs-supplements/cyclophosphamide-oral-route-intravenous-route/description/drg-20063307

Cyclophosphamide (oral route, intravenous route) Cyclophosphamide interferes with the growth of cancer cells, which are then destroyed by the body. Since the growth of normal body cells may ...