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Clinical Trial of BP1001(Liposomal Grb2 Antisense Oligonucleotide) in Combination With Decitabine in AML / High Risk MDS

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ClinicalTrials.gov Identifier: NCT02781883
Recruitment Status : Recruiting
First Posted : May 25, 2016
Last Update Posted : June 13, 2019
Sponsor:
Information provided by (Responsible Party):
Bio-Path Holdings, Inc.

Brief Summary:
The primary objective of this study is to assess whether the combination of BP1001 and decitabine provides greater efficacy (Complete Remission [CR], Complete Remission with incomplete hematologic recovery [CRi], Complete Remission with partial hematologic recovery [CRh], than decitabine alone (by historical comparison) in participants with AML/High Risk MDS that cannot or elect not to be treated with more intensive chemotherapy. The historical comparison to be used will be defined in the Statistical Analysis Plan (SAP) prior to database closure.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia (AML) High-risk Myelodysplastic Syndrome Drug: BP1001 in combination with decitabine Phase 2

Detailed Description:

Improvement of clinical benefit in fragile AML and high risk MDS patients while maintaining tolerability is an important area of further clinical development. Modern aggressive combination chemotherapy can induce CR in a significant proportion of patients with previously untreated AML or high risk MDS, but relapse occurs in most unless patients undergo intensive allogeneic hematopoietic stem cell transplantation. Novel therapies are needed for these patients

The Grb2 gene has been mapped to the human chromosome region 17q22-qter, a region that is duplicated in leukemias and solid tumors, which may result in an increased copy number of the Grb2 gene product. As Grb2 is important for the transformation of murine hematopoietic cells, and the proliferation of human leukemia cells that express high levels of oncogenic tyrosine kinases, inhibition of Grb2 may have a significant impact on the natural history of leukemias. The study drug (BP1001) may be able to inhibit the cells from making Grb-2. Researchers hope that without this protein, the leukemia cells will die.

This represents an area in which targeted therapies might be of benefit to these patients. One such potential treatment is BP1001, liposomal anti-sense treatment directed against Growth Factor Receptor-Bound Protein 2 (Grb2). Decitabine is approved in Europe for the treatment of adult patients with newly diagnosed de novo or secondary acute myeloid leukemia (AML). In vitro studies in AML cells co-incubated with BP1001 and decitabine suggests that treatment of AML patients with decitabine followed by BP1001 may be a combination that could benefit patients with AML.

This Phase IIa, multicenter, study of BP1001 in combination with decitabine will enroll participants with AML or high risk MDS who are not otherwise eligible for standard or high-intensity chemotherapy regimens or who have elected a low-intensity regimen.

This trial will utilize an open label, two-stage design to assess the safety profile, PK, PD, and efficacy of of BP1001 in combination with decitabine to assess whether the combination of either provides greater efficacy than decitabine alone.

This 2-arm combination cohort study of BP1001 with decitabine in either untreated or relapsed/refractory patients with AML or high risk MDS will have 19 evaluable patients enrolled per cohort, with a decision to stop or proceed to 54 patients per cohort, for a total of 108 additional patients.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase IIa, Open-label, Clinical Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of BP1001 in Combination With Decitabine in AML or High Risk MDS Patients Who Are Ineligible for Intensive Induction Therapy
Study Start Date : May 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2021


Arm Intervention/treatment
Experimental: Untreated AML/High Risk MDS
BP1001 in combination with decitabine
Drug: BP1001 in combination with decitabine
BP1001 in combination with decitabine
Other Names:
  • Liposomal Grb-2
  • L-Grb-2

Experimental: Refractory/Relapsed AML/High Risk MDS
BP1001 in combination with decitabine
Drug: BP1001 in combination with decitabine
BP1001 in combination with decitabine
Other Names:
  • Liposomal Grb-2
  • L-Grb-2




Primary Outcome Measures :
  1. Assessment of efficacy by bone marrow aspirate or biopsy [ Time Frame: 180 days ]
    Assess whether the combination of BP1001 and decitabine provides greater efficacy (Complete Remission [CR], Complete Remission with incomplete hematologic recovery [CRi], Complete Remission with partial hematologic recovery [CRh], than decitabine alone (by historical comparison) in participants with AML/High Risk MDS


Secondary Outcome Measures :
  1. Assessment of safety of BP1001 in combination with decitabine [ Time Frame: 30 days ]
    Evaluate safety and toxicity of the combination of BP1001 with decitabine using non-hematologic and hematologic measures per NCI CTCAE criteria (with a safety run-in)

  2. Assessment of the pharmacokinetics (PK) of BP1001 when given in combination with decitabine [ Time Frame: 30 days ]
    Evaluate the in vivo PK using plasma to compute half life and elimination.

  3. Assessment of Minimal Residual Disease (MRD) status in patients who achieve CR/CRi/CRh with BP1001 + decitabine; [ Time Frame: 30 days ]
    Assess time to response from administration of BP1001+decitabine to CR, CRi, or CRh, negative MRD status as defined by the site and as available (Usually ≤ 0.1% by multi-parameter flow cytometry).

  4. Assessment of Partial Remissions and blast count reductions. [ Time Frame: 30 days ]
    Assessment of Partial Remissions (per Cheson, 2003), and blast count reductions (per Williams, 2016)

  5. Assessment of overall survival [ Time Frame: 180 days ]
    To assess event-free survival, overall survival, time to response, and duration of response from date of study entry to study closure or death.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

At the time of Screening, participants must meet all of the following criteria to be considered eligible to participate in the study:

  1. Adults ≥18 years of age
  2. Females must be of non-childbearing potential, surgically sterile, postmenopausal, or practice adequate methods of contraception during the study and for 30 days after the last dose of study drug or decitabine
  3. Males must agree to use an adequate method of contraception during the study and for at least 30 days after the last dose of study drug, or decitabine
  4. Histologically documented diagnosis (based on the 2008 World Health Organization [WHO] Classification) (Vardiman 2009) of one of the following:

    1. Newly diagnosed untreated AML; or
    2. Untreated secondary AML, including AML that has progressed from MDS
    3. In some cases of AML associated with specific genetic abnormalities, however, the diagnosis of AML may be made if the blast count is less than 20% (Dohner, 2017) - specifically AML with t(15;17), t(8;21), inv(16), or t(16;16))
    4. Relapsed or Refractory AML/High Risk MDS
    5. Untreated High Risk MDS
  5. Investigator considers participant ineligible for (or unwilling to receive) intensive induction therapy based on medical reasons, disease characteristics such as genetics, type of AML (untreated or secondary), or participant characteristics such as age, performance status, co-morbidities, organ dysfunctions, or patient election of low-intensity treatment.
  6. Eligible for decitabine therapy, based on Investigator assessment; although decitabine is not approved by FDA for AML, it is commonly used in this patient population and is approved for MDS patients.
  7. Adequate hepatic and renal functions as defined by:

    1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times the upper limit of normal (ULN); and
    2. Usually total bilirubin ≤ 1.5 ULN. In specific cases the PI may request a waiver of this requirement with medical justification and agreement with the medical monitor and Bio-Path Holdings. And;
    3. Estimated glomerular filtration rate (eGFR) of at least 40 ml/min. These estimations can be calculated using the following methods (Appendix D):

    i. Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation OR ii. Cockcroft Gault equation OR iii. Modification of Diet in Renal Disease (MDRD study equation) OR iv. Creatinine clearance estimated by 24-hr urine collection for creatinine clearance

  8. Documented Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  9. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic treatment (with the exception of alopecia), based on Investigator assessment
  10. Willing and able to provide written informed consent

Exclusion Criteria:

At the time of Screening, participants who meet any of the following criteria will be excluded from participating in the study:

  1. Active non-hematologic or lymphoid malignancy other than AML or High Risk MDS treated with immuno- or chemotherapy within the previous 12 months except active non-melanoma, non- invasive skin cancer will be allowed.
  2. Known, active leptomeningeal leukemia requiring intrathecal therapy. NOTE: Patients with a history of CNS disease may be allowed to participate based on at least 1 documented, negative spinal fluid assessment within 28 days prior to Screening
  3. Isolated potentially treatable extramedullary leukemia without also meeting bone marrow criteria for acute leukemia (for AML usually = 20% blasts in bone marrow aspirate or biopsy). Patients may have leukemia with lower blast counts (Dohner, 2017). Bio-Path Holdings and Investigator concurrence required.
  4. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) PML-RARA
  5. Chronic myeloid leukemia (CML) in any phase
  6. Receipt of any anti-cancer therapy within 14 days prior to C1D1, with the exception of hydroxyurea or anagrelide (within 24 hours), TKI (within 1day), or single dose of cytarabine (for proliferative disease)
  7. Palliative treatment for high WBCs with hydroxyurea (HU) is allowed.
  8. Uncontrolled active, untreated, or progressive infection
  9. Receipt of any investigational agent or study treatment within 30 days prior to C1D1
  10. Females who are capable of becoming pregnant, test positive for pregnancy, or are breast-feeding during the Screening period, or intend to become pregnant or breast-feed during the course of the study or within 30 days after last dose of study drug
  11. Serious intercurrent medical or psychiatric illness which, in the opinion of the Investigator, would interfere with the ability of the participant to complete the study
  12. Known active or clinically significant hepatitis B infection (based on positive surface antigen [HBsAg]), hepatitis C infection (based on positive antibody [HCV Ab]), or human immunodeficiency virus (HIV-1 or HIV-2, based on positive antibody)
  13. History of any hypersensitivity to decitabine, unless reaction is deemed irrelevant to the study by the Investigator and Medical Monitor
  14. Presence of concurrent conditions that, in the opinion of the Investigator and/or Medical Monitor, may compromise the participant's ability to tolerate study treatment or interfere with any aspect of study conduct or interpretation of results. This includes, but is not limited to, unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled and sustained hypertension, clinically significant cardiac dysrhythmia or clinically significant baseline ECG abnormality (e.g., QTcF >470 msec)
  15. Within the past 6 months, has had any of the following: myocardial infarction, unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack
  16. Uncontrolled seizure disorder (i.e., seizures within the past 2 months)
  17. Unable or unwilling to communicate or cooperate with the Investigator or follow the protocol for any reason

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02781883


Contacts
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Contact: Maro Ohanian, DO 713-792-2631 mohanian@mdanderson.org

Locations
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United States, Kansas
University of Kansas Cancer Center Recruiting
Fairway, Kansas, United States, 66205
Contact: Kerry Hepler, RN    913-945-7552    khepler@kumc.edu   
Contact: Jecinta Scott, MS    913-945-7505    jscott11@kumc.edu   
Principal Investigator: Tara Lin, MD         
United States, New Jersey
New Jersey Hematology Oncology Associates Recruiting
Brick, New Jersey, United States, 08724
Contact: Apurv Agrawal, MD       agrawalmd@gmail.com   
United States, New York
Weill Cornell Medical College - New York - Presbyterian Hospital Recruiting
New York, New York, United States, 10021
Contact: Gail J Roboz, MD    646-962-2700    gar2001@med.cornell.edu   
Principal Investigator: Gail J Roboz, MD         
United States, Texas
University of Texas M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Maro Ohanian, DO    713-792-2631    mohanian@mdanderson.org   
Principal Investigator: Maro Ohanian, MD         
Baylor Scott & White Research Institute Recruiting
Temple, Texas, United States, 76508
Contact: Niki Watson    254-724-2111    Niki.Watson@BSWHealth.org   
Contact: Dedra Preece    254-724-2111    Dedra.Preece@BSWHealth.org   
Principal Investigator: Kathleen Halka, MD         
Sub-Investigator: Christian T Cable, MD         
Sub-Investigator: Vinit G Karur, MD         
Sub-Investigator: Mark Holguin, MD         
Sub-Investigator: Rakesh Surapaneni, MD         
United States, West Virginia
West Virginia University/Mary Babb Randolph Cancer Center Recruiting
Morgantown, West Virginia, United States, 26506
Contact: Michael Craig, MD    304-293-0609    craigm@wvumedicine.org   
Sponsors and Collaborators
Bio-Path Holdings, Inc.
Investigators
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Principal Investigator: Maro Ohanian, DO M.D. Anderson Cancer Center

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Responsible Party: Bio-Path Holdings, Inc.
ClinicalTrials.gov Identifier: NCT02781883     History of Changes
Other Study ID Numbers: BP1001-201-AML
First Posted: May 25, 2016    Key Record Dates
Last Update Posted: June 13, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Bio-Path Holdings, Inc.:
Liposomal Grb-2 treatment of AML or High Risk MDS
Liposomal Grb-2 with decitabine for AML or High Risk MDS
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors