Tretinoin + Arsenic Trioxide (+/- Gemtuzumab) for Leukemia

Recruiting at 4 trial locations

Overseen By Farhad Ravandi-Kashani

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: QTcF interval > 480ms, High creatinine, High bilirubin, High ALT/AST

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

151 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a drug combination, including tretinoin and arsenic trioxide, for individuals with newly diagnosed acute promyelocytic leukemia, a type of blood cancer. The trial will assess whether adding gemtuzumab ozogamicin, a drug targeting specific cancer cells, can improve treatment outcomes. Researchers aim to determine if this combination can more effectively stop cancer cells from growing and spreading. Suitable participants have confirmed acute promyelocytic leukemia and have not yet received full treatment. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to significant advancements in leukemia treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether 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 using tretinoin, arsenic trioxide, and gemtuzumab ozogamicin together is generally safe for treating acute promyelocytic leukemia. One study successfully cured 94% of patients with this combination, reporting very few serious side effects. Another study found that using just tretinoin and arsenic trioxide was also very effective and had low side effects, even over a long period. This suggests that the treatment is usually well-tolerated, with serious side effects being rare. Overall, the evidence indicates that this treatment is safe for most patients, although individual experiences may vary. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for leukemia, which often rely on chemotherapy and targeted therapies, the combination of tretinoin and arsenic trioxide offers a unique approach by using these distinct active ingredients together. Tretinoin, a form of vitamin A, promotes the maturation of leukemia cells, while arsenic trioxide induces cancer cell death. The potential addition of gemtuzumab ozogamicin, an antibody-drug conjugate, targets leukemia cells specifically, enhancing the attack on the cancer. Researchers are excited about these treatments because they offer a promising alternative for patients, potentially leading to better outcomes with a different mechanism of action compared to traditional options.

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

In this trial, participants will receive a combination of tretinoin and arsenic trioxide, which studies have shown to be effective in treating acute promyelocytic leukemia. This combination outperforms tretinoin with standard chemotherapy, as research indicates these two drugs help stop leukemia cells from growing and spreading. Additionally, some participants will receive gemtuzumab ozogamicin, a targeted drug that may increase the number of cancer cells killed without affecting normal cells. Overall, this treatment approach has produced excellent results in many patients with this type of leukemia. ^{1 6 7 8 9}

Who Is on the Research Team?

Farhad Ravandi-Kashani

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with a new diagnosis of acute promyelocytic leukemia (APL) confirmed by specific genetic tests. Participants must understand the study and agree to sign consent forms. Those who have started emergency APL treatment can join, and women of childbearing age need negative pregnancy tests before and during the study. Contraception use is required for all sexually active participants.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of the study

I started emergency treatment for APL, including ATRA, ATO, or idarubicin.

I agree to use two effective birth control methods during the study.

Exclusion Criteria

Patients with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3 times upper limit of normal unless felt to be related the underlying leukemia by the treating physician or hemolysis or Gilbert's disease

Fridericia corrected QT (QTcF) interval on the electrocardiogram (EKG) greater than 480 milliseconds

Patients with creatinine > 2.5 times upper limit of normal unless felt to be related the underlying leukemia by the treating physician or hemolysis or Gilbert's disease

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive tretinoin orally twice daily, arsenic trioxide intravenously over 1-2 hours daily, and gemtuzumab ozogamicin intravenously over 2 hours once at weeks 1-4

4 weeks

Consolidation

Patients achieving complete response receive arsenic trioxide IV 5 days per week during weeks 1-4, 9-12, 17-20, and 25-28 and tretinoin PO BID for 2 weeks on and 2 weeks off. Treatment repeats every 8 weeks for up to 4 courses

32 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Arsenic Trioxide
• Gemtuzumab Ozogamicin
• Tretinoin

Trial Overview The trial is testing how well tretinoin and arsenic trioxide work together, with or without an additional drug called gemtuzumab ozogamicin, in treating newly diagnosed APL patients. The goal is to see if adding gemtuzumab ozogamicin can kill more cancer cells without harming normal cells.

How Is the Trial Designed?

Group I: Treatment (tretinoin, arsenic trioxide, gemtuzumab ozogamicin) Experimental Treatment 4 Interventions

INDUCTION: Patients receive tretinoin PO BID, arsenic trioxide IV over 1-2 hours daily, and gemtuzumab ozogamicin IV over 2 hours once at weeks 1-4. CONSOLIDATION: Patients achieving CR receive arsenic trioxide IV 5 days per week during weeks 1-4, 9-12, 17-20, and 25-28 and tretinoin PO BID for 2 weeks on and 2 weeks off. Treatment repeats every 8 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Arsenic Trioxide is already approved in United States, European Union for the following indications:

Approved in United States as Trisenox for:

• Acute promyelocytic leukemia (APL)

Approved in European Union as Trisenox for:

• Acute promyelocytic leukemia (APL)

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Arsenic trioxide is highly effective in treating acute promyelocytic leukemia (APL), achieving complete remissions in over 80% of relapsed patients and molecular remission in 90% of those who reach complete remission.

Clinical trials indicate that arsenic trioxide not only benefits relapsed APL patients but also shows promise in first-line treatment and consolidation therapy, improving event-free and overall survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New data with arsenic trioxide in leukemias and myelodysplastic syndromes. Sekeres, MA.[2019]

Arsenic trioxide, combined with low-dose ara-C, was tested in a phase I/II trial involving 113 patients (49 with myelodysplastic syndrome and 64 with acute myeloid leukemia), showing that the treatment was generally well tolerated and led to complete remissions in both groups.

This combination therapy demonstrated efficacy even in patients with poor baseline health and unfavorable genetic profiles, highlighting arsenic trioxide's potential as a valuable treatment option for high-risk blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arsenic and old lace: novel approaches in elderly patients with acute myeloid leukemia. Roboz, GJ.[2018]

In a study of 481 patients with untreated acute promyelocytic leukemia (APL), the addition of arsenic trioxide (As(2)O(3)) to standard treatment significantly improved event-free survival at 3 years (80% vs. 63%).

Patients receiving As(2)O(3) also showed better disease-free survival rates (90% vs. 70% at 3 years), indicating that As(2)O(3) is an effective consolidation treatment for newly diagnosed APL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Powell, BL., Moser, B., Stock, W., et al.[2021]

Arsenic trioxide (AT) has shown high efficacy in treating acute promyelocytic leukemia (APL), achieving complete remission in 80% to 90% of patients with refractory or relapsed cases, while being well tolerated at a dose of 0.15 mg/kg/d.

Common side effects include fatigue, rash, and QTc-interval prolongation, but ongoing research is exploring its combination with retinoic acid and potential use in other blood cancers and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arsenicals in hematologic cancers. Novick, SC., Warrell, RP.[2018]

The novel oral formulation ORH-2014 of arsenic trioxide was found to be safe and well-tolerated in a phase 1 study involving 12 patients with advanced hematologic malignancies, with no dose-limiting toxicities and only one instance of grade III QT prolongation that resolved after treatment interruption.

At a dose of 15 mg, ORH-2014 achieved comparable plasma concentrations to the standard intravenous arsenic trioxide, indicating it provides similar therapeutic exposure while being easier to administer, making it a promising candidate for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral arsenic trioxide ORH-2014 pharmacokinetic and safety profile in patients with advanced hematologic disorders. Ravandi, F., Koumenis, I., Johri, A., et al.[2021]

Arsenic trioxide (As2O3) combined with all-trans retinoic acid (ATRA) successfully achieved complete molecular remission in a patient with secondary, relapsed, resistant promyelocytic leukemia, despite the patient's severe complications.

The treatment was notable for its lack of significant toxicity, allowing the patient to undergo a bone marrow autograft after reaching complete remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Arsenic and all-trans retinoic acid as induction therapy before autograft in a case of relapsed resistant secondary acute promyelocytic leukemia. Galimberti, S., Papineschi, F., Carmignani, A., et al.[2018]

In a study of 20 patients with acute promyelocytic leukemia (APL), the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) resulted in a high complete remission (CR) rate of 94.4%, with 17 out of 18 evaluable patients achieving CR.

The treatment was well-tolerated, showing no significant side effects, indicating that this combination therapy is both effective and safe for APL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Preliminary observation of the combination of arsenic trioxide and all-trans retinoic acid for the treatment of acute promyelocytic leukemia]. Zhao, YZ., Li, HQ., Li, DP., et al.[2018]

Arsenic trioxide is a key treatment for acute promyelocytic leukemia and shows effectiveness against other leukemia types, but its side effects can limit its use, particularly in patients with complex symptoms.

Combining arsenic trioxide with other anticancer drugs, vitamins, and plant products can help reduce side effects and improve treatment outcomes, highlighting the need for careful clinical application to maximize benefits and minimize risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of arsenic trioxide-involved combined treatment algorithms for leukemia: basic concepts and clinical implications. Jiang, Y., Shen, X., Zhi, F., et al.[2023]

In a study of 129 adult patients with acute promyelocytic leukemia (APL), maintenance therapy using ATRA, arsenic trioxide, and ascorbic acid (AAA) demonstrated a favorable safety profile with no severe organ toxicities and resulted in high long-term survival rates, with 5-year overall survival at 94%.

The maintenance therapy led to a low relapse rate of 13% over a median follow-up of 100 months, indicating that AAA is effective in maintaining first complete remission (CR1) in APL patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral arsenic trioxide, all-trans retinoic acid, and ascorbic acid maintenance after first complete remission in acute promyelocytic leukemia: Long-term results and unique prognostic indicators. Gill, HS., Yim, R., Kumana, CR., et al.[2021]

Arsenic trioxide (ATO) showed a complete remission (CR) rate of 97.5% in 41 patients with acute promyelocytic leukemia (APL), which is comparable to the 93.3% CR rate seen with all-trans retinoic acid (ATRA) in 30 patients.

ATO therapy resulted in a significantly shorter median time to complete remission (29 days) compared to ATRA (38.5 days), and ATRA was associated with a high incidence of retinoic acid syndrome (52.9%), suggesting ATO may be a safer and more effective first-line treatment for APL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Comparison of efficacy and adverse effects between arsenic trioxide and all-trans retinoic acid in patients with acute promyelocytic leukemia]. Jiao, L., Wang, SJ., Zhuang, JL., et al.[2018]

Citations

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Long-term outcome of acute promyelocytic leukemia treated ... The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of ...

2. ashpublications.org ashpublications.org/blood/article-abstract/129/10/1275/36003

Long-term outcome of acute promyelocytic leukemia treated ... The combination of all-trans-retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the ...

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Long‐term follow‐up of a phase 2 study of all‐trans retinoic ... All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combinations have produced excellent outcomes in patients with standard-risk acute ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01409161?term=AREA%5BInterventionSearch%5D(%22Tretinoin%22)&rank=2

Study Details | Tretinoin and Arsenic Trioxide With or ... Giving tretinoin and arsenic trioxide together with gemtuzumab ozogamicin may kill more cancer cells. Detailed Description. PRIMARY OBJECTIVES: I. Assess ...

5. nature.com nature.com/articles/s41408-022-00753-y

An effective and chemotherapy-free strategy of all-trans ... The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39584789/

Long-term follow-up of a phase 2 study of all-trans retinoic ... The combination of ATO-ATRA and GO was curative in 94% of patients who had APL with a favorable safety profile.

7. pnas.org pnas.org/doi/10.1073/pnas.0813280106

Long-term efficacy and safety of all-trans retinoic acid ... These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up.

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Effective Treatment of Acute Promyelocytic Leukemia With ... We examined the outcome of patients with newly diagnosed acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and arsenic trioxide ...

9. tandfonline.com tandfonline.com/doi/full/10.2147/OTT.S100513

Retinoic acid and arsenic trioxide in the treatment of acute ... The discovery of acute promyelocytic leukemia (APL) arose from early case reports of patients who presented with an acute leukemia and ...