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Protocol Details

A Phase 1, Dose Escalation, Safety and Tolerability Study of NX- 2127, a Bruton's Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: N/A

Referral Letter Required


Population Exclusion(s)



R/R Chronic Lymphocytic Leukemia (CLL);
Small Lymphocytic Lymphoma (SLL);
study drug treatment;

Recruitment Keyword(s)



Relapsed/Refractory B-cell Malignancies

Investigational Drug(s)


Investigational Device(s)



Drug: NX-2127 (BTK degrader)

Supporting Site

National Heart, Lung, and Blood Institute


Blood cancers that affect B cells are often treated with drugs that block or inhibit a protein in cancer cells called BTK. Some tumors become resistant to these drugs. Researchers want to learn if a new drug (NX-2127) that degrades BTK can help.


To learn if NX-2127 can be used to treat certain B-cell blood cancers.


Adults aged 18 and older with certain B-cell blood cancers who have received at least 2 prior treatments that failed (or 1 for people with Waldenstrom macroglobulinemia [WM]). Cancer types include diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, and WM.


Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

PET and/or CT scans

Heart tests

Lymph node biopsy, if needed

Bone marrow biopsy/aspirate, if needed

Participants will take NX-2127 by mouth once daily or every-other day. They will fast for 2 hours before and after taking the drug. On some days, they will fast overnight. They will take the drug until they have bad side effects or their cancer gets worse.

Participants will have weekly study visits for the first 2 months of treatment. Some visits may last 8 hours or more. For the next 2 months, they will have visits every 2 weeks. After that, they will have monthly visits. At visits, they will repeat some screening tests.

Participants will have safety follow-up visits 7 and 30 days after treatment ends. Then they will have follow-up visits in person or by phone every 3 months for 1 year.

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-Patients must be >= 18 years of age.

-Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, WM, MCL, MZL, FL (grade 1 - 3b), or DLBCL (high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements and high-grade B- cell lymphoma NOS).

-Patients in Phase 1a must meet the following:

--Received at least 2 prior systemic therapies (or 1 prior therapy for patients with WM) and have no other therapies known to provide clinical benefit

--At least 2 weeks must have elapsed between the last therapy and the first dose of study drug or at least 4 weeks for antibody-containing therapies, except for patients with CLL on a small molecule therapy who require at least 5 half-lives or 2 days (whichever is longer)

--Must require systemic therapy

-Patients in Phase 1b (Dose Expansion) must have one of the following histologically documented R/R B-cell malignancies where treatment failed is defined as: i.) Best response of stable disease (SD) during treatment and then subsequently had progressive disease (PD); ii.) Any response with secondary progression; or iii) Best response of PD at any time while on therapy:

--CLL/SLL with no BTK C481 mutation whose disease has failed treatment with a BTKi;

--BTK C481 mutation-positive CLL/SLL whose disease has failed treatment with a BTKi;

--MCL or MZL whose disease has failed treatment with BTKi and anti-CD20 mAb-based regimen or WM whose disease has failed treatment with BTKi;

--FL whose disease has failed treatment with anti-CD20 mAb-based regimen;

--DLBCL whose disease has failed treatment with anti-CD20 mAb-based regimen and an anthracycline (either progressed post stem cell transplant or transplant-ineligible) [see exclusion #6 for prior CAR-T therapy].

---High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements and high-grade B-cell lymphoma NOS

-Patients must have radiographically measurable disease per response criteria specific to the malignancy (i.e., iwCLL, IWG, or Lugano Classification of Lymphoma response criteria) by computed tomography (CT) or CT/positron emission tomography (CT/PET) scan, defined as at least one node > 1.5 cm in size or measurable extranodal lesion of >= 1.0 cm in longest diameter. Evaluable disease in bone marrow or compartment (pleural effusion) is also allowed.

-Patients in Phase 1b must have received at least 2 prior lines of systemic therapy for the management of their disease (or 1 prior therapy for patients with WM)

-Patients with indolent forms of NHL must meet the criteria requiring systemic treatment (i.e., iwCLL, IWG, or Lugano Classification of Lymphoma response criteria).

-Patients with transformed lymphoma are eligible for the study with the exception of those described in exclusion #1.

-Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

-Adequate organ and bone marrow function, in the absence of G-CSF and GM-CSF growth factors, as defined by the following laboratory parameters. Safety assessments, including clinical laboratory tests, are required to be repeated on Cycle 1 Day 1 only for patients for whom Screening assessments were performed more than 48 hours prior to Cycle 1 Day 1. Patients must continue to meet eligibility criteria through dosing on Cycle 1 Day 1.


---Hemoglobin > 9 g/dL (a 7-day transfusion free interval is required)

---Absolute neutrophil count (ANC) > 1.0 (SqrRoot) 10^9/L (> 0.75 (SqrRoot) 10^9/L in Phase 1b)

---Platelets > 75 (SqrRoot) 10^9/L (>50 (SqrRoot) 10^9/L if bone marrow involvement)

---Coagulation INR and PTT/aPTT <= 1.5 (SqrRoot) ULN


---Serum Amylase <= 1.5 (SqrRoot) ULN

---Serum Lipase <= 1.5 (SqrRoot) ULN


---Aspartate aminotransferase and alanine aminotransferase <= 2.5 (SqrRoot) upper limit of normal (ULN)

---Total bilirubin <= 1.5 (SqrRoot) ULN (or <= 5 (SqrRoot) for patients with Gilbert s syndrome)


---Serum creatinine < 1.5 (SqrRoot) ULN or a calculated glomerular filtration rate (GFR) greater than 45 mL/min/1.73mm^2. CDK-EPI creatinine


---QT interval ECG QT interval corrected for heart rate (QTc) < 475 msec, measured by Fridericia's formula [QTcF = QT/(RR^0.33)]. If the QTc is prolonged in a patient with a pacemaker or bundle branch block, the patient may be enrolled in the study if confirmed by the medical monitor.


---Blood oxygen saturation (SPO2) > 92% on room air

-Women of childbearing potential (WOCBP) and all males who are sexually active with WOCBP must use two forms of contraception, of which 1 must be highly effective (defined as < 1% failure rate per year) and 1 must be a barrier method as described in Inclusion criterion 13, throughout the study from Screening through 3 months after the final dose of study drug. WOCBP defined as per the 2014 Clinical Trial Facilitation Group recommendations on contraception and pregnancy testing in clinical trials. Link to website: About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf

-Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study drug. Men must agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug.

-A male patient who is sexually active with a WOCBP must agree to use a barrier method of birth control e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

-Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.

-Each patient must sign an informed consent form (ICF) indicating that he or she understands the purpose of procedures required for the study and are willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the patient s disease.


Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:

-Richter s transformation, prolymphocytic leukemia, or blastoid transformation of FL into DLBCL prior to planned start of study drug

-History of CNS lymphoma/leukemia in remission for less than 2 years

-Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia

-History of known/suspected other autoimmune disease (exception(s): patients with vitiligo, resolved childhood atopic dermatitis, hypothyroidism, or hyperthyroidism that is clinically euthyroid at screening are allowed.)

-Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of study drug

-Patient has any of the following:

--Uncontrolled intercurrent illness including, but not limited to, persistent poorly controlled hypertension (defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite optimal medical management)

--Uncontrolled diabetes

--Ongoing significant infection requiring systemic antibiotics, antifungals or antivirals (with exception of HIV antivirals) in the last 7 days

--Patients who have undergone autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug

--Patients with active graft-versus-host disease (GVHD) or on anti-GVHD treatment or prophylaxis

--History of CAR-T therapy within 100 days prior to start of study drug. Must have evidence of B cell recovery if patient received prior CAR-T therapy.

--History of known or suspected seizure disorder

-Bleeding diathesis, or other known risk for acute blood loss

-History of Grade >= 2 hemorrhage within 28 days

-Patients requiring ongoing treatment with warfarin or patients treated with dual anti-platelet therapy and vitamin K antagonists

-Prior radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation)

-Prior chemotherapy within 2 weeks of planned start of study drug

-Prior monoclonal antibody therapy within 4 weeks of planned start of study drug

-Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy, or hematologic parameters meeting inclusion criteria).

-Patients with a history of significant skin rash secondary to lenalidomide treatment should be discussed with the Medical Monitor to determine eligibility.

-Active known second malignancy with the exception of any of the following:

--Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer;

--Adequately treated Stage I cancer from which the patient is currently in remission and has been in remission for >= 2 years;

--Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 ng/mL; or

--Any other cancer from which the patient has been disease-free for >= 2 years

-Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy and hormonal prophylaxis for a prior malignancy)

-Patient has known allergies, hypersensitivity, or intolerance to components of study drug.

-Patient is pregnant, breastfeeding or planning to become pregnant while enrolled in this study or within 3 months after the last dose of study drug; for WOCBP, negative pregnancy status must be confirmed by pregnancy test at Screening and within 24 hours of first dose of study drug.

-Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.

-Patient has had major surgery (e.g., requiring general anesthesia) within 4 weeks before the planned first dose of study drug, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 4 weeks after the last dose of study drug. Note: patients with minor planned surgical procedures to be conducted under local anesthesia may participate.

-Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or COVID-19 vaccination within 14 days prior to first dose of study drug. Vaccinations of any kind are prohibited during the DLT period.

-Infection with human immunodeficiency virus (HIV)-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm3 and undetectable viral load) are eligible.

-Current active liver disease from any cause, including hepatitis B (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with HBV who are negative for HBV DNA by quantitative PCR are eligible irrespective of serology findings.

-Active viral reactivation (e.g., Cytomegalovirus (CMV) or Epstein Barr virus (EBV))

-Use of systemic corticosteroids (> 20 mg/day prednisone or equivalent) within 15 days (except for prophylaxis for radio diagnostic contrast reactions), or other immunosuppressive drugs within 30 days, prior to start of the study

-Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 micrograms (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 (Micro)g/day or less are eligible for study entry.)

-Any of the following within 6 months of planned start of study drug:

--Myocardial infarction;

--Unstable angina;

--Unstable symptomatic ischemic heart disease;

--Placement of a coronary arterial stent;

--Uncontrolled atrial fibrillation or other clinically significant arrhythmias or conduction abnormalities;

--New York Heart Association (NYHA) class III or IV heart failure;

--Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events);

--Stroke or intracranial hemorrhage;

--Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease)

-Any other medical or psychiatric condition or social situation that, in the opinion of the investigator, would compromise patient safety, or interfere with the objectives or the protocol or completion of treatment per protocol

-For 14 days prior to first dose of study drug treatment (or 5 half-lives, whichever is longer), administration of any strong or moderate cytochrome P450 3A (CYP3A) inducers, strong or moderate CYP3A inhibitors, or inhibitors of P-glycoprotein

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Not Provided

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Principal Investigator

Referral Contact

For more information:

Adrian U. Wiestner, M.D.
National Heart, Lung and Blood Institute (NHLBI)
NIHBC 10 - CRC BG RM 3-5140
(301) 594-6855

Pia Nierman, R.N.
National Heart, Lung and Blood Institute (NHLBI)
National Institutes of Health
Building 10
Room 4-5350
10 Center Drive
Bethesda, Maryland 20892
(301) 827-1094

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1

Clinical Trials Number:


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