Chronic Lymphocytic LeukemiaPhase 1NCT03454165
A Study of BNC105P Combined With Ibrutinib
A Phase 1 study testing BNC105P and Ibrutinib in people with Chronic Lymphocytic Leukemia, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
Trial summary
A Phase I Trial of BNC105P in combination with BTK inhibitor ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia(CLL). This study proposes that ibrutinib will have far greater efficacy when it is combined with drugs that kill the CLL cells in peripheral circulation, thereby preventing them from… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Lymphocytic Leukemia
- What is being tested?
- BNC105P and Ibrutinib
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- 9 Mar 2018to 14 Jan 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients who are > 18 years of age, must have histologically or flow cytometry confirmed diagnosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to NCI-WG 1996 guidelines. The malignant B cells must co-express CD5 with CD19 or CD20. Patients who lack CD23 expression on their leukemia cells should be examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma. Patients with CLL who have progressed on prior ibrutinib therapy will be eligible. Patients with B-cell prolymphocytic leukemia and patients with Richter's transformation of CLL/SLL are NOT eligible.
- Active disease meeting at least 1 of the IWCLL 2008 criteria for requiring treatment:
- A minimum of any one of the following constitutional symptoms:
- Unintentional weight loss >10% within the previous 6 months prior to screening.
- Extreme fatigue (unable to work or perform usual activities).
- Fevers of greater than 100.5 F for ≥2 weeks without evidence of infection.
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- Night sweats without evidence of infection. ii) Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia or thrombocytopenia.
- Massive (i.e., >6 cm below the left costal margin), progressive or symptomatic splenomegaly.
- Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive lymphadenopathy.
- Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of less than 6 months.
- Autoimmune anemia or thrombocytopenia that is poorly responsive to corticosteroids.
- Patients must have received at least one prior therapy for CLL comprised of the following:
- ≥1 regimen containing an anti-CD20 antibody (e.g., rituximab, obinutuzumab) administered for ≥ 2 doses ii) ≥1 regimen containing ≥1 cytotoxic agent (eg, bendamustine, fludarabine, chlorambucil, cyclophosphamide) administered for ≥ 2 cycles
- Patients must have ECOG performance status ≤2.
- Patients must have organ function as defined below:
- direct bilirubin ≤2 X institutional ULN (unless due to known Gilbert's syndrome or compensated hemolysis directly attributable to CLL) ii) AST or ALT less than 2.5 X institutional ULN iii) estimated CrCL using the Cockroft-Gault equation ≥50 mL/min (see formula in Appendix 2).
- platelets ≥50,000/mm3 independent of transfusion support, with no active bleeding, and absolute neutrophil count ≥1000/mm3, unless due to disease involvement in the bone marrow.
- Ability to understand and the willingness to sign a written informed consent document.
- Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin or urine pregnancy test at screening.
- All patients of reproductive potential (heterosexually active men and women) must agree to a use of a barrier method of contraception and a second method of contraception and men must agree not to donate sperm during the study and for 4 weeks after receiving the last dose of study treatment.
Who cannot join
- Prior therapeutic intervention with any of the following:
- nitrosoureas or mitomycin C within 6 weeks;
- therapeutic anticancer antibodies (including rituximab) within 4 weeks;
- radio- or toxin-immunoconjugates within 10 weeks;
- all other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy.
- Inadequate recovery from adverse events related to prior therapy to grade ≤1 (excluding Grade 2 alopecia and neuropathy).
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- Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent.
- Stem cell transplant recipients must have no evidence of active graft-versus-host disease.
- Use of full dose, therapeutic anti-coagulation with warfarin.
- Concomitant use of strong CYP inducers or inhibitors including nutraceutical preparations, e.g., grapefruit juice and St John's Wort
- History prior malignancy except:
- Malignancy treated with curative intent and no known active disease present for ≥ 2 years prior to initiation of therapy on current study;
- adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease;
- adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease;
- asymptomatic prostate cancer managed with "watch and wait" strategy;
- myelodysplastic syndrome which is clinically well controlled and no evidence of the cytogenetic abnormalities characteristic of myelodysplasia on the bone marrow at screening.
- Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test in absence of hemolysis or history of immune-mediated cytopenias are not exclusions).
- Thrombotic events (pulmonary embolism; deep venous thrombosis) within 6 month prior to start of therapy.
- History of Human Immunodeficiency Virus (HIV) infection or active hepatitis B or C. Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B serology. If patients receiving routine IVIG have core antibody or surface antigen positivity without evidence of active viremia (negative hepatitis B DNA) they may still participate in the study, but should have hepatitis serologies and hepatitis B DNA monitored periodically by the treating physician.
- Patients with the following cardiovascular abnormalities:
- Corrected QT interval (QTc) >500 msec within 7 days prior to registration for protocol therapy. NOTE: if QTc is >450 and ≤500 msec, subject to local cardiology review and approval, the patient may be enrolled if the QTc elevation is deemed clinically insignificant.
- Acute cardiovascular events within 6 months prior to C1D1: stroke (transient ischemic attack permitted), acute coronary syndrome, peripheral arterial obstruction, clinically significant arrhythmias (e.g., such as paroxysmal atrial fibrillation/atrial flutter, sick sinus syndrome, second or third degree atrio-ventricular blockade). A cardiology consultation may be obtained to clarify clinical significance.
- Clinical cardiac heart failure of New York Heart Association Class III or IV or left ventricular ejection fraction (LVEF) <50% as assessed by echocardiogram at screening.
- Major surgery (requiring general anesthesia) within 30 days prior to initiation of therapy.
- Inability to swallow and retain an oral medication. Patients with clinically significant medical condition of malabsorption, inflammatory bowel disease, chronic conditions which manifest with diarrhea, refractory nausea, vomiting or any other condition that will interfere significantly with the absorption of ibrutinib are excluded.
- Any condition for which participation in the study is judged by the Investigator to be detrimental to the patient with inter-current illness including, but not limited to an uncontrolled active infection; unstable angina pectoris; uncontrolled cardiac arrhythmia or psychiatric/social situations that would jeopardize compliance with study requirements.
Trial locations and contacts
1 site in 1 country.
United States1 site
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire, 03756
About this study
Official title: A Phase 1 Trial of BNC105P & Ibrutinib in Patients w/ Relapsed/Refractory CLL
A Phase I Trial of BNC105P in combination with BTK inhibitor ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia(CLL). This study proposes that ibrutinib will have far greater efficacy when it is combined with drugs that kill the CLL cells in peripheral circulation, thereby preventing them from returning to the protective lymph node niche. The study will establish the maximum tolerated dose(MTD) of the combination of BNC105P with ibrutinib, characterize the pharmacodynamic effects of BNC105P alone and in combination with ibrutinib in CLL cells, and provide preliminary assessment of the efficacy of the combination in CLL.
The study consists of a Screening Period with baseline tumor assessment before BNC105P administration, a Treatment Period with up to six 21-day cycles and Follow-up Period. Subjects will receive a total of six cycles of therapy unless treatment is discontinued
Read the detailed description
A Phase I Trial of BNC105P in combination with BTK inhibitor ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Ibrutinib inhibits the pro-survival BCR signaling of CLL cells in the stromal niche resulting in their egress to the periphery. Importantly, if administration of ibrutinib is stopped, the CLL cells rapidly return to the lymph node. In some patients, the drug-induced increase in circulating CLL cells has been seen for more than a year reflecting the fact that the cells do not readily die once they exit the lymph node. Resistance to ibrutinib has been observed as mutations in the drug-binding cysteine in its target, BTK. This resistance is likely to become far more prevalent as patients remain on ibrutinib for months or years. We propose that ibrutinib will have far greater efficacy when it is combined with drugs that kill the CLL cells in peripheral circulation, thereby preventing them from returning to the protective lymph node niche. BNC105P works through an entirely different mechanism, i.e. tipping the balance of pro-survival and pro-apoptotic BCL2 family member proteins toward the latter, resulting in cell death. This pathway of apoptosis occurs at all stages of the cell cycle which is important considering that the majority of peripheral CLL cells are non-cycling (in G0).
The study consists of a Screening Period with baseline tumor assessment before BNC105P administration, a Treatment Period with up to six 21-day cycles and Follow-up Period. Subjects will receive a total of six cycles of therapy unless treatment is discontinued.
- Conditions
- Chronic Lymphocytic Leukemia
- Being tested
- BNC105P, Ibrutinib
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BNC105PCombination product
BNC105P is the phosphate ester of BNC105, a small molecule tubulin polymerization inhibitor.
IbrutinibCombination product
A novel BTK inhibitor.
| Study group | Role | What they receive |
|---|---|---|
| Single Arm | Experimental | Evaluate the MTD of BNC105P in combination with ibrutinib in patients with relapsed/refractory CLL. Treatment will be administered on an outpatient basis but will also be permitted inpatient. BNC105P will be administered as a single agent prior to initiation of ibrutinib. Beginning with cycle 2, ibrutinib will be administered concomitantly with BNC105P at a starting dose of 420 mg PO daily. Each cycle will last for 21 days. Provided no toxicities occur, each patient will be treated for 6 cycles. Receives: Combination Product: BNC105P; Combination Product: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
To establish the maximum tolerated dose and toxicity of BNC105P plus Ibrutinib
The number of relapsed refractory chronic lymphatic leukemia patients, in cohorts of 3-6, who develop treatment related adverse effects from combined therapy with BNC105P and ibrutinib. The treatment related adverse events will be defined based on CTCAE v 4.0
Measured: Two years
Secondary outcomes (3)
Evaluating the efficacy of BNC105P combined with Ibrutinib in patients with CLL
The number of relapsed refractory CLL patients in each dosing cohort (n= 3-6 patients) who when treated with BNC105P combined with ibrutinib will have therapeutic benefit based on CLL response criteria using CT imaging
Measured: Two years
Determine the Overall Response Rate (ORR)
Overall response rate (ORR) will be determined based on the number of study participants who achieve CR, CRi, PR or nPR assessed two months after completion of therapy, as per IWCLL 2008 criteria.
The timeframe is consistent with the Measure Title
Measured: Two years
Determine the event free survival
Event-free survival (EFS), defined as the interval between the date of first study treatment and the date of objective signs of disease recurrence, subsequent anti-leukemic therapy, or death, whichever is first reported.
Measured: Two years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Mar 2018
- Study start9 Mar 2018
- Primary completion14 Jan 2021
- Study completion14 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Chronic Lymphocytic LeukemiaStudies of the same condition, open and under way.
- More trials run by Dartmouth-Hitchcock Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Model description
- Open label dose escalation study, with a Storer D ; 3-3 cohort design
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dartmouth-Hitchcock Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Lionel.D.Lewis, MD, Dartmouth-Hitchcock Medical Center
- Investigators
- Lionel D Lewis, MD, Principal investigator, Dartmouth-Hitchcock Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03454165
- Sponsor's protocol ID
- D17093
- Status last verified
- Jan 2023
- First submitted
- 26 Jan 2018
- Last updated
- 4 Jan 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 4 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1 Trial of BNC105P & Ibrutinib in Patients w/ Relapsed/Refractory CLL
- ClinicalTrials.gov ID
- NCT03454165
- Acronym / sponsor ID
- D17093
- Conditions
- Chronic Lymphocytic Leukemia
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Dartmouth-Hitchcock Medical CenterUniversity, hospital or other
- Study start
- 9 Mar 2018 (actual)
- Primary completion
- 14 Jan 2021 (actual)
- Study completion
- 14 Jan 2021 (actual)
- First posted
- 5 Mar 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A Phase I Trial of BNC105P in combination with BTK inhibitor ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia(CLL). This study proposes that ibrutinib will have far greater efficacy when it is combined with drugs that kill the CLL cells in peripheral circulation, thereby preventing them from returning to the protective lymph node niche. The study will establish the maximum tolerated dose(MTD) of the combination of BNC105P with ibrutinib, characterize the pharmacodynamic effects of BNC105P alone and in combination with ibrutinib in CLL cells, and provide preliminary assessment of the efficacy of the combination in CLL.
The study consists of a Screening Period with baseline tumor assessment before BNC105P administration, a Treatment Period with up to six 21-day cycles and Follow-up Period. Subjects will receive a total of six cycles of therapy unless treatment is discontinued
Detailed description
A Phase I Trial of BNC105P in combination with BTK inhibitor ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Ibrutinib inhibits the pro-survival BCR signaling of CLL cells in the stromal niche resulting in their egress to the periphery. Importantly, if administration of ibrutinib is stopped, the CLL cells rapidly return to the lymph node. In some patients, the drug-induced increase in circulating CLL cells has been seen for more than a year reflecting the fact that the cells do not readily die once they exit the lymph node. Resistance to ibrutinib has been observed as mutations in the drug-binding cysteine in its target, BTK. This resistance is likely to become far more prevalent as patients remain on ibrutinib for months or years. We propose that ibrutinib will have far greater efficacy when it is combined with drugs that kill the CLL cells in peripheral circulation, thereby preventing them from returning to the protective lymph node niche. BNC105P works through an entirely different mechanism, i.e. tipping the balance of pro-survival and pro-apoptotic BCL2 family member proteins toward the latter, resulting in cell death. This pathway of apoptosis occurs at all stages of the cell cycle which is important considering that the majority of peripheral CLL cells are non-cycling (in G0).
The study consists of a Screening Period with baseline tumor assessment before BNC105P administration, a Treatment Period with up to six 21-day cycles and Follow-up Period. Subjects will receive a total of six cycles of therapy unless treatment is discontinued.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open label dose escalation study, with a Storer D ; 3-3 cohort design
| Arm | Type | Receives |
|---|---|---|
| Single Arm | Experimental | Combination Product: BNC105P, Combination Product: IbrutinibEvaluate the MTD of BNC105P in combination with ibrutinib in patients with relapsed/refractory CLL. Treatment will be administered on an outpatient basis but will also be permitted inpatient. BNC105P will be administered as a single agent prior to initiation of ibrutinib. Beginning with cycle 2, ibrutinib will be administered concomitantly with BNC105P at a starting dose of 420 mg PO daily. Each cycle will last for 21 days. Provided no toxicities occur, each patient will be treated for 6 cycles. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Patients who are > 18 years of age, must have histologically or flow cytometry confirmed diagnosis of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to NCI-WG 1996 guidelines. The malignant B cells must co-express CD5 with CD19 or CD20. Patients who lack CD23 expression on their leukemia cells should be examined for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out mantle cell lymphoma. Patients with CLL who have progressed on prior ibrutinib therapy will be eligible. Patients with B-cell prolymphocytic leukemia and patients with Richter's transformation of CLL/SLL are NOT eligible.
- Active disease meeting at least 1 of the IWCLL 2008 criteria for requiring treatment:
- Unintentional weight loss >10% within the previous 6 months prior to screening.
- Extreme fatigue (unable to work or perform usual activities).
- Fevers of greater than 100.5 F for ≥2 weeks without evidence of infection.
Key exclusion criteria (26 listed)
- Prior therapeutic intervention with any of the following:
- nitrosoureas or mitomycin C within 6 weeks;
- therapeutic anticancer antibodies (including rituximab) within 4 weeks;
- radio- or toxin-immunoconjugates within 10 weeks;
- all other chemotherapy, radiation therapy within 3 weeks prior to initiation of therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BNC105PBNC105P is the phosphate ester of BNC105, a small molecule tubulin polymerization inhibitor. | Combination product | Single Arm |
| IbrutinibA novel BTK inhibitor. | Combination product | Single Arm |
Primary outcome
To establish the maximum tolerated dose and toxicity of BNC105P plus Ibrutinib
Time frame: Two years
The number of relapsed refractory chronic lymphatic leukemia patients, in cohorts of 3-6, who develop treatment related adverse effects from combined therapy with BNC105P and ibrutinib. The treatment related adverse events will be defined based on CTCAE v 4.0
3 secondary outcomes
Evaluating the efficacy of BNC105P combined with Ibrutinib in patients with CLL
Time frame: Two years
Determine the Overall Response Rate (ORR)
Time frame: Two years
Determine the event free survival
Time frame: Two years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jan 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lionel D Lewis, MD principal investigator
Dartmouth-Hitchcock Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing BNC105P and Ibrutinib in people with Chronic Lymphocytic Leukemia, run by Dartmouth-Hitchcock Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
To establish the maximum tolerated dose and toxicity of BNC105P plus Ibrutinib (time frame: Two years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jan 2023.