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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and examine the side effects of combining olaparib (Lynparza) with high-dose chemotherapy for certain types of lymphoma that have returned or don't respond to treatment. The researchers focus on whether this combination is more effective than chemotherapy alone, particularly for patients undergoing a stem cell transplant. Eligible participants have lymphoma that has recurred after treatment or hasn't responded to previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

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

Previous studies have generally shown that olaparib is well-tolerated, though some patients experienced serious side effects like high blood pressure and bone marrow issues. About 31% of patients taking olaparib with another drug had serious reactions. Vorinostat, used alone for certain blood cancers, was mostly safe, with most patients not experiencing severe problems. Past studies have shown that gemcitabine was well-tolerated, with no patients experiencing severe infections or bleeding related to the treatment.

Busulfan carries a warning about potential reproductive risks and cancer, but past studies have not linked it to liver problems when used alone. Melphalan often causes a drop in white blood cell counts, weakening the body's defense against infections. Close monitoring of patients is important when using these treatments.

Each drug has its own safety profile. Patients should discuss potential risks and benefits with their doctors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for lymphoma because it combines olaparib, a PARP inhibitor, with high-dose chemotherapy and a stem cell transplant. Unlike standard chemotherapy treatments, which attack cancer cells directly, olaparib works by blocking a protein that cancer cells need to repair their DNA, making them more susceptible to the chemotherapy. This approach not only targets the cancer more effectively but also may enhance the overall effectiveness of the treatment. Additionally, the use of multiple drugs like busulfan, gemcitabine, melphalan, and vorinostat in a coordinated regimen offers a targeted assault on the cancer cells, potentially leading to better outcomes for patients. This combination, which includes a stem cell transplant, is a novel approach that may provide a new lifeline for those with resistant forms of lymphoma.

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

In this trial, participants will receive a combination of treatments, including olaparib. Research shows that olaparib has potential in treating various cancers by preventing cancer cells from repairing themselves. Studies have found it can help some cancer patients live longer. Vorinostat, another drug in this trial, has helped about 40% of lymphoma patients, with some achieving full or partial recovery. Gemcitabine, also part of the treatment regimen, has been useful for patients whose lymphoma has returned, with about 37% responding to the treatment. Busulfan and melphalan, often used together in this trial, effectively prepare patients for stem cell transplants, helping them survive longer. These drugs might work better together to treat lymphomas that have returned or are resistant to treatment. ^{6 7 8 9 10}

Who Is on the Research Team?

Yago L. Nieto

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4031688/

Intravenous Busulfan Plus Melphalan Is a Highly Effective ... Among 49 patients with HL, 38 were alive at a median follow-up of 34 months (range 4-51) with 1- and 2-year OS rates of 90% and 85%, respectively (Figure 1).

2. hematologyadvisor.com hematologyadvisor.com/news/busulfan-myeloproflierative-neoplasms-mpn-favorable-efficacy-safety-treatment/

Real-World Data Shows Favorable Efficacy and Safety ... Researchers determined busulfan treatment of MPNs demonstrated high response rates and infrequent adverse events.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35381164/

Busulfan, Melphalan, and Etoposide (BuME) Showed an ... We reported the busulfan, melphalan, and etoposide (BuME) conditioning regimen was effective in patients with relapsed or high-risk NHL.

4. astctjournal.org astctjournal.org/article/S1083-8791(16)00167-1/fulltext

Comparison of a Multicenter Phase II Study and CIBMTR ... The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT00238433

Busulfan, Melphalan, and Thiotepa in Treating Patients ... RATIONALE: Chemotherapy, such as busulfan, melphalan, and thiotepa, may destroy cancerous blood-forming cells (stem cells) in the blood and bone marrow.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2003/09386slr023_myleran_lbl.pdf

MYLERAN® - accessdata.fda.gov With the present analysis of the data, no cases of hepatotoxicity have appeared in the busulfan-alone arm of the study. Long-term continuous therapy with.

7. medsafe.govt.nz medsafe.govt.nz/profs/datasheet/m/Mylerantab.pdf

DATA SHEET Studies of busulfan treatment in animals have shown reproductive toxicity (see. Preclinical Safety Data). The potential risk for humans is largely unknown ...

8. pubchem.ncbi.nlm.nih.gov pubchem.ncbi.nlm.nih.gov/compound/Busulfan

Busulfan | C6H14O6S2 | CID 2478 - PubChem - NIH 1,4-Butanediol dimethanesulfonate (Busulfan) can cause cancer according to California Labor Code. It can cause developmental toxicity according to an ...

9. acs.org acs.org/molecule-of-the-week/archive/b/busulfan.html

Busulfan Chemical Safety Warning. Carcinogenicity, category 1A, H350—May cause cancer, Chemical Safety Warning. *Compilation of multiple safety data ...

10. reference.medscape.com reference.medscape.com/drug/myleran-busulfex-busulfan-342104

Myleran, Busulfex (busulfan) dosing, indications, ... Other Indications & Uses. CML associated with Philadelphia chromosome. PEDIATRIC. Safety and efficacy not established ... data informing drug-associated risk; ...