Olaparib + Chemotherapy for Lymphoma

Overseen By Yago Nieto, MD, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: HIV, Hepatitis B, Pregnancy, others

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

Compensation: Varies

Number of Visits: 3

Duration: 14 days

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of olaparib when given together with high-dose chemotherapy in treating patients with lymphomas that have come back or does not treatment and are undergoing stem cell transplant. Drugs used in chemotherapy, such as olaparib, vorinostat, gemcitabine, busulfan, and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as rituximab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving olaparib and high-dose chemotherapy together may work better in treating patients with relapsed/refractory lymphomas undergoing stem cell transplant than with chemotherapy alone.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for specific drugs. If you are taking strong or moderate CYP3A inhibitors or inducers, you will need to stop them 2 to 5 weeks before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Olaparib + Chemotherapy for Lymphoma?

Research shows that the combination of gemcitabine, busulfan, and melphalan, when enhanced with the drug olaparib, significantly inhibits the growth of lymphoma cells by preventing DNA repair and promoting cell death. This combination has shown promising results in preclinical studies, suggesting it could be effective for lymphoma patients undergoing stem cell transplantation. ^{1 2 3 4 5}

What safety data exists for the combination of Olaparib and chemotherapy in humans?

Olaparib, when used for different cancers, can cause side effects like fatigue, anemia (low red blood cell count), nausea, and vomiting. These side effects vary in severity depending on the type of cancer being treated. In some cases, reducing the dose and using additional medications can help manage these side effects. ^{1 4 5 6 7}

What makes the Olaparib + Chemotherapy treatment for Lymphoma unique?

This treatment combines Olaparib, a drug that targets cancer cells by interfering with their DNA repair mechanisms, with chemotherapy drugs like Busulfan, Gemcitabine, and Melphalan, which are used to kill cancer cells. The combination aims to enhance the effectiveness of chemotherapy by making cancer cells more vulnerable to damage, offering a novel approach compared to standard chemotherapy alone. ^{8 9 10 11 12}

Research Team

Yago L. Nieto

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults aged 18-65 with certain types of relapsed or refractory lymphomas, including T-cell and B-cell non-Hodgkin's lymphoma, Hodgkin's lymphoma, and diffuse large B-cell lymphoma. Participants must have adequate organ function and not be eligible for higher priority transplant protocols. They should not be pregnant or breastfeeding, able to swallow pills, free from serious infections or other health conditions that could affect participation.

Inclusion Criteria

Prothrombin time </=1.5 x institutional upper limit of normal

Provision of informed consent prior to any study specific procedures

Patients must have a life expectancy >/= 16 weeks

Exclusion Criteria

Pregnancy

Patients with a known hypersensitivity to olaparib or any of the excipients of the product

My heart's electrical activity is abnormal, or I have a family history of long QT syndrome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib, vorinostat, gemcitabine, busulfan, melphalan, and undergo stem cell transplant

14 days

Daily visits for drug administration

Immediate Follow-up

Participants are monitored closely for safety and adverse events

30 days

Every 1-2 days

Extended Follow-up

Participants are monitored for long-term outcomes and survival

Up to 100 days

Every 2 weeks

Long-term Follow-up

Participants are monitored for event-free survival and overall survival

2 years

Treatment Details

Interventions

• Busulfan
• Gemcitabine
• Melphalan
• Olaparib
• Peripheral Blood Stem Cell Transplantation
• Rituximab
• Vorinostat

Trial Overview The trial tests the combination of olaparib with high-dose chemotherapy (including vorinostat, gemcitabine, busulfan, melphalan) versus standard treatment in patients undergoing stem cell transplantation. It aims to determine the safety and optimal dosage of olaparib when used alongside these chemotherapeutic agents.

Participant Groups

Group I: Treatment (olaparib, high-dose chemotherapy, transplant) Experimental Treatment 8 Interventions

Patients receive olaparib PO BID on days -11 to -3, vorinostat PO on days -10 to -3, gemcitabine IV over 4.5 hours on days -9 and -4, busulfan IV over 3 hours on day -9 to -6, melphalan IV over 30 minutes on days -4 and -3, and undergo peripheral blood stem cell transplant IV over 30-60 minutes on day 0. Patients with CD20+ tumors also receive rituximab IV over 3-6 hours on day -10.

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

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

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+

Findings from Research

In a study of 83 breast cancer patients undergoing chemotherapy with doxorubicin-cyclophosphamide, both aprepitant (APT) and olanzapine (OLP) were effective in preventing chemotherapy-induced nausea and vomiting, with complete response rates of 81% for APT and 85% for OLP in the acute period.

OLP showed a lower incidence of severe vomiting compared to APT, with 50% of OLP patients experiencing severe vomiting versus 81% in the APT group, suggesting that OLP may provide a safer profile for managing nausea and vomiting in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study. Shivaprakash, G., Udupa, KS., Sarayu, V., et al.[2018]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines. [2023]

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

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas. [2022]

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

Autologous stem cell transplantation for refractory or poor-risk relapsed Hodgkin's lymphoma: effect of the specific high-dose chemotherapy regimen on outcome. [2022]

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

The PARP inhibitor olaparib enhances the cytotoxicity of combined gemcitabine, busulfan and melphalan in lymphoma cells. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Cladribine, gemcitabine, busulfan, and SAHA combination as a potential pretransplant conditioning regimen for lymphomas: A preclinical study. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Comparison of Adverse Reactions Caused by Olaparib for Different Indications. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

[Olaparib Could Be Re-Administered after Chemotherapy]. [2023]

8. India pubmed.ncbi.nlm.nih.gov

Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Effect of olanzapine for breast cancer patients resistant to triplet antiemetic therapy with nausea due to anthracycline-containing adjuvant chemotherapy. [2018]

10. Japan pubmed.ncbi.nlm.nih.gov

[Elucidation of Influential Factors on Nausea Associated with Olaparib Administration]. [2021]

11. Germany pubmed.ncbi.nlm.nih.gov

Multiple-day administration of fosaprepitant combined with tropisetron and olanzapine improves the prevention of nausea and vomiting in patients receiving chemotherapy prior to autologous hematopoietic stem cell transplant: a retrospective study. [2022]

12. Germany pubmed.ncbi.nlm.nih.gov

A pooled analysis of adding olanzapine to guideline-recommended antiemetic therapy for breast cancer patients treated with an anthracycline and cyclophosphamide in prospective and retrospective studies. [2022]