Reduced intensity bone marrow transplant for high-risk solid tumors

A Phase II Trial of Reduced Intensity Conditioning and Partially HLA-mismatched (HLA-haploidentical) Related Donor Bone Marrow Transplantation for High-risk Solid Tumors

This study is testing a new way to use a less intense chemotherapy and a special type of bone marrow transplant to help people with very high-risk solid tumors fight their cancer.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 1 Year to 50 Years
• Sex: All
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, cyclophosphamide, radiation, Fludarabine
• Locations: 3 sites (Baltimore, Maryland and 2 other locations)
• Trial ID: NCT01804634 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the safety and feasibility of a reduced intensity chemotherapy regimen combined with haploidentical bone marrow transplantation for patients with very high-risk solid tumors. The approach leverages the graft-versus-tumor effect, utilizing T cell and NK cell mediated responses to combat refractory cancers. Participants will receive a unique post-transplant immunosuppression regimen that includes cyclophosphamide and a shortened duration of tacrolimus. The study is designed to be broadly applicable, as most patients will have a half-matched donor available, such as a parent or sibling.

Who should consider this trial

Good fit: Ideal candidates are patients aged 1 to 50 years with high-risk solid tumors and a suitable haploidentical bone marrow donor.

Not a fit: Patients with low-risk solid tumors or those without a haploidentical donor may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with high-risk solid tumors who currently have limited treatment alternatives.

How similar studies have performed: Other studies have shown promising results with similar haploidentical transplantation approaches, indicating potential for success in this novel application.

Eligibility criteria

Presence of a suitable related HLA-haploidentical bone marrow donor.a. The donor and recipient must be identical at at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.

1 year-50 years

Patients must have a confirmed histopathologic diagnosis and be classified as high risk defined by having an expected survival of \< 10%. Examples include:

* Neuroblastoma or ganglioneuroblastoma

  * Failure to achieve at least a PR after induction therapy with COG ANBL0532 or standard chemotherapy
  * Refractory to induction chemotherapy with COG ANBL0532 or standard chemotherapy
  * Patients with high risk disease as defined in Appendix 1 whose autologous peripheral blood stem cell product is contaminated with neuroblastoma or who do not have an autologous product available
  * Patients with high risk disease as defined in Appendix 1 who do not meet eligibility requirements/organ function requirements for myeloablative conditioning. Patients with \>5 identified lesions on the end of induction (COG ANBL0532 or standard chemotherapy) MIBG scan
* Stage 4 rhabdomyosarcoma
* Metastatic Ewing Sarcoma
* Osteosarcoma with metastatic disease beyond the lungs and/or with lung metastases not amenable to resection
* Desmoplastic small round cell tumor
* Any other solid tumor and soft tissue sarcoma with an estimated \<10% chance of survival will be considered on a case by case basis at the departmental tumor board and/or sarcoma meeting

Previous therapy:

* It is expected that patients will have received upfront standard of care therapy for their respected disease
* Patients who relapse after either single or tandem autologous BMT are eligible (\> 6 months must have elapsed from start of last BMT).
* Patients must be recovered from the acute toxicities of any prior chemo/radio/immunotherapy or BMT

Patients do not need to have measurable disease at time of enrollment. Patients with measurable disease must have stable disease by RECIST criteria on two scans at least 6 weeks apart.

Patients with adequate organ function as measured by

* Cardiac: Left ventricular ejection fraction at rest must be ≥ 35%, or shortening fraction \> 25%.
* Hepatic: Bilirubin ≤ 3.0 mg/dL; and ALT, AST, and Alkaline Phosphatase \< 5 x ULN.
* Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or GFR) \> 40 mL/min/1.73m2.
* Pulmonary: FEV1, FVC, DLCO (diffusion capacity) \> 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation \> 92% on room air.

Good performance status (Karnofsky/Lansky 60-100)

Patients (Parents/guardians for those \<18) and donors must be able to sign consent forms.

Patients must be willing to participate in all stages of treatment

Criteria for recipient ineligibility Patients will not be excluded on the basis of sex, racial or ethnic background.

HIV-positive

Donor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available.

Positive leukocytotoxic crossmatch

Women of childbearing potential who currently are pregnant (HCG+) or who are not practicing adequate contraception

Uncontrolled viral, bacterial, or fungal infections.

Criteria for donor eligibility Age \>0.5 years

Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).

Lack of recipient anti-donor HLA antibody Note: In some instances, low level, non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a level well below that detectable by flow cytometry. This will be decided on a case-by-case basis by the PI and one of the immunogenetics directors.

In the event that two or more eligible donors are identified, the following order of priority will be used to determine the preferred donor:

1. Medically and psychologically fit and willing to donate
2. Killer Immunoglobulin Receptor (KIR) Haplotype B Donor
3. Red blood-cell compatibility (in order of preference)

   1. RBC cross-match compatible
   2. Minor ABO incompatibility
   3. Major ABO incompatibility
4. For CMV seronegative recipients, a CMV seronegative donor. For CMV seropositive recipients, a CMV seropositive donor is preferred.
5. When possible, HLA-mismatched donors will be prioritized over HLA-matched to maximize an allogeneic benefit.

If more than one preferred donor is identified from the above list and there is no medical reason to prefer one of them, then the following guidelines are recommended:

1. If the patient is male, choose a male donor
2. Choose the youngest preferred donor
3. If the patient and family express a strong preference for a particular donor, use that one.

Where this trial is running

Baltimore, Maryland and 2 other locations

• The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins — Baltimore, Maryland, United States (Recruiting)
• Albert Einstein College of Medicine, Children's Hospital at Montefiore — The Bronx, New York, United States (Recruiting)
• New York Medical Center/ Maria Fareri Children's Hospital — Valhalla, New York, United States (Recruiting)

Study contacts

• Principal investigator: Heather Symons, MD, MHS — Johns Hopkins University
• Study coordinator: Heather Symons, MD, MHS

Conditions Refractory and/or Relapsed Metastatic Solid Tumors; Solid Tumors; Neuroblastoma; Osteosarcoma; Ewing Sarcoma; Rhabdomyosarcoma; Hepatoblastoma; Desmoplastic Round Cell Tumor