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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), non-GCB DLBCL, or PCNSL.

-Patients in Phase 1a must meet the following:

--Received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) 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 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 and have failed at least 2 prior treatments (at least 1 prior therapy for WM or PCNSL) and meet the appropriate criteria listed below in A-E; treatment failed is defined as: i.) Best response of stable disease (SD) during treatment and then subsequently had progressive disease; ii.) Any response with secondary progression; or iii) Best response of progressive disease 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 whose disease has failed treatment with BTKi and anti-CD20 mAb-based regimen

--FL (grade 1-3b) or MZL whose disease has failed treatment with anti-CD20 mAb-based regimen; or PCNSL whose disease has failed treatment with a BTKi

--Non-GCB DLBCL whose disease has failed treatment with anti-CD20 mAbbased regimen and an anthracycline (either progressed post stem cell transplant or transplant-ineligible) (see exclusion #6 for prior chimeric antigen receptor-T cell [CAR-T] therapy) or WM whose disease has failed treatment with BTKi 5. Patients must have radiographically measurable disease per response criteria specific to the malignancy (i.e., iwCLL, International Working Group [IWG], Lugano Classification of Lymphoma, or International PCNSL Collaborative Group response criteria) by computed tomography (CT) or CT/positron emission tomography (CT/PET) or MRI, defined as at least one node > 1.5 cm in size or measurable extranodal lesion of >= 1.0 cm in longest diameter. Other quantifiable disease (such as bone marrow infiltration, minimal residual disease, splenic enlargement) is also allowed. For PCNSL, measurable disease includes the presence of contrast enhancing parenchymal lesions on MRI (CT with contrast is allowed when MRI is medically contra-indicated), cerebrospinal fluid (CSF) cytology positive for lymphomatous involvement, and/or the presence of intraocular disease by ophthalmologic examination. Disease evaluation at screening should be done per disease standard guidelines. Subsequent procedures for the purpose of response assessments may be carried out per institutional standard and as clinically indicated.

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

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

Patients with PCNSL should meet the criteria for treatment as per the PCNSL Collaborative Group 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 (non-PCNSL indications) or 0-2 (PCNSL patients).

- Adequate organ and bone marrow function as defined by the following laboratory parameters (hematology, hepatic and renal laboratory parameters are required to be performed 10 days prior to Cycle 1 Day 1 and must meet the criteria below.)

Laboratory Parameter Value


---Hemoglobin > 9 g/dL or > 7 g/dL if anemia is due to bone marrow involvement per investigator assessment. A minimum 5-day transfusion-free interval is required.

---Absolute neutrophil count (ANC) > 1.0 x 10^9/L unless neutropenia is due to bone marrow involvement per investigator assessment. Granulocyte colony stimulating factor (G-CSF) is allowed for those with bone marrow involvement of disease.

---Platelets > 75 x 10^9/L or > 50 (SqrRoot) 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement per investigator assessment. A minimum 14-day transfusion-free interval is required. Use of platelet-derived growth factors are prohibited.

---Coagulation (international normalized ratio [INR] and partial thromboplastin time [PTT] or activated partial thromboplastin time [aPTT]) <= 1.5 (SqrRoot) upper limit of normal (ULN)

(Patients undergoing lumbar puncture must have either

PTT or aPTT < ULN)


---Serum amylase <=(SqrRoot) ULN

Serum lipase <=1.5 (SqrRoot) ULN


---Aspartate aminotransferase & alanine aminotransferase <=2.5 (SqrRoot) ULN

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


---Serum creatinine < 1.5 (SqrRoot) ULN or a calculated GFR greater than 45mL/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 > 92% on room air

-Women of childbearing potential (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 (condom), throughout the study from Screening through 6 months after the final dose of study drug. WOCBP defined as per the 2020 Clinical Trial Facilitation Group recommendations.

- Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 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 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 (condom with spermicidal foam/gel/film/cream/suppository) throughout the study from Screening through 3 months after the final dose of study drug.

- 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:

Prolymphocytic leukemia, MCL with blastoid histology, MCL with pleomorphic morphology, or MCL with known TP53 mutation.

- History of central nervous system (CNS) lymphoma/leukemia in remission for less than 2 years (non-PCNSL indications) or evidence of disease outside of the CNS (other than ocular involvement) or disease involving the brain stem (PCNSL patients).

- Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia.

- History of known/suspected other autoimmune disease (exception(s): patients with alopecia, 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 (non-PCNSL indications) or poorly controlled seizures (PCNSL patients)

-- History of prior pneumonitis requiring steroid treatment

- 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 an equivalent vitamin K antagonist and within 7 days prior to first dose of study drug.

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

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

- Prior anti-cancer monoclonal antibody therapy within 4 weeks of planned start of study drug and prior anti-cancer small molecule therapy within 2 days or 5 half-lives (whichever is longer).

- 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.

- 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 6 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 coronovirus-19 (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/mm 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 hepatitis B virus (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 exceeding 20 mg/day prednisone (or equivalent) for non-PCNSL indications within 15 days prior to study start. PCNSL patients may not exceed corticosteroid doses of 40 mg/day prednisone (or equivalent) and should be on a stable or decreasing dose for 7 days prior to study start. One-time corticosteroid doses used as prophylaxis for radio diagnostic contrast reactions are allowed.

- Use of non-steroidal 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 microg (Note: Patients who switch from a high dose to a dose of 30 microg/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 uncontrolled 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.

-Administration of any strong inducers or inhibitors of cytochrome P450 3A (CYP3A) for 14 days (or 5 half-lives, whichever is longer) prior to the first dose of study drug, any moderate inducers of CYP3A for 7 days (or 5 half-lives, whichever is longer), and inhibitors of P-glycoprotein for 7 days (or 5 half-lives, whichever is longer).

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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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