B-cell Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Small Lymphocytic Lymphoma
Conditions
Keywords
Chronic lymphocytic leukemia, Small lymphocytic lymphoma, Mantle cell lymphoma, Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1), Bruton Tyrosine Kinase (BTK), Ibrutinib, Marginal zone lymphoma
Brief summary
This is Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab, when given in combination with ibrutinib in patients with B-cell lymphoid malignancies. Cirmtuzumab is a monoclonal antibody that attaches to a protein (called ROR 1) that is found on hematologic tumor cells. ROR1 has been shown to play a role in cell signaling that cause leukemia and lymphoma cells to grow and survive. ROR1 is rarely found on healthy cells.
Detailed description
This is a Phase 1b/2 study to investigate the safety and effectiveness of the investigational drug, cirmtuzumab (INN:zilovertamab), when given in combination with ibrutinib in patients with B-cell lymphoid malignancies. The Phase 1b will be conducted in two parts (Part 1 and Part 2). Part 1 is a dose-finding evaluation of the sequential administration of cirmtuzumab monotherapy followed by cirmtuzumab and ibrutinib combination therapy in chronic lymphocytic leukemia /small lymphocytic leukemia (CLL/SLL), previously treated mantle cell lymphoma (MCL) subjects that are BTKI naiive or have received a prior Bruton tyrosine kinase (BTK) inhibitor therapy, unless they demonstrated primary or acquired resistance to BTKi. Up to 48 subjects will be enrolled in Part 1 to determine the recommended dosing regimen (RDR). In Part 2, up to 60 subjects (CLL/SLL, MCL and MZL (marginal zone lymphoma) will be enrolled to further evaluate the safety and pharmacology of the cirmtuzumab and ibrutinib combination given at the RDR determined in Part 1 of the study. MZL subjects that have been previously treated and have relapsed after or progressed during at least one prior anti-CD20 -based therapy will be evaluated. In the Phase 2 (Part 3) portion of the study, approximately 30 subjects with CLL/SLL who may have received minimal prior BTK inhibitor therapy will be randomized to either Arm 1 (cirmtuzumab and ibrutinib) at the RDR or Arm 2 (ibrutinib alone) to evaluate the clinical activity and safety of the two arms.
Interventions
DRUGCirmtuzumab (2-16 kg/mg) plus Ibrutinib
Participants will receive escalating doses of cirmtuzumab (2-16 mg/kg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily, starting at week 4.
DRUGCirmtuzumab (300mg) plus Ibrutinib
Participants will receive cirmtuzumab (300 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.
DRUGCirmtuzumab (600 mg) plus ibrutinib
Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 5 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.
DRUGCirmtuzumab (RDR) plus ibrutinib
Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 or 560 mg) orally once daily
DRUGCirmtuzumab plus ibrutinib
Arm A: Participants will receive cirmtuzumab (600 mg) administered IV every 2 weeks for 3 administrations and then every 4 weeks thereafter, plus ibrutinib (420 mg) orally once daily.
DRUGIbrutinib alone
Arm B: Participants will receive ibrutinib (420 mg) orally once daily
Sponsors
California Institute for Regenerative Medicine (CIRM)
University of California, San Diego
Pharmacyclics LLC.
Oncternal Therapeutics, Inc
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women of age ≥18 years. 2. ECOG performance status of 0, 1, or 2 3. Histological diagnosis of CLL/SLL, MCL or MZL (including splenic,nodal and extranodal subtypes) as documented in medical records (pathology reports and slides or blocks should be available for review or additional testing). 4. MCL has been previously treated and has relapsed after or progressed during prior therapy. CLL/SLL may have been previously treated or are treatment naïve but now require therapy. MZL has been previously treated and has relapsed after or progressed during at least one prior anti-CD20 -based therapy 5. A medically appropriate candidate for ibrutinib treatment (based on the judgement of the clinical investigator). 6. Patients who have received prior BTK inhibitor therapy are eligible, unless they demonstrated primary or acquired resistance to a BTK inhibitor or experienced a serious or severe adverse event attributed to BTK inhibitor therapy. 7. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid malignancy (defined as the presence of ≥1 non-biopsied, non-irradiated lesion that measures \>1.5 cm in the longest dimension \[LD\] and ≥1.0 cm in the longest perpendicular dimension \[LPD\] as assessed by computed tomography \[CT\] or magnetic resonance imaging \[MRI\]). 8. Current medical need for therapy due to disease-related symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or progressive disease. 9. Completion of all previous therapy (including any Bcl-2 or PI3K inhibitor therapy, surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of cancer ≥1 week (or ≥3 half-lives of the previous drug) before the start of study therapy. 10. All acute toxic effects of any prior antitumor therapy resolved to Grade ≤1 before the start of study therapy (with the exceptions of alopecia, or neurotoxicity \[Grade 1 or 2 permitted\], or selected laboratory parameters \[Grade 1 or Grade 2 permitted with exceptions as noted below\]). 11. Adequate bone marrow function: 1. Absolute neutrophil count (ANC) ≥1.0 × 109/L. 2. Platelet count ≥50 × 109/L. 3. Hemoglobin ≥8.0 g/dL maintained for ≥1 week from any prior transfusion. 12. Adequate hepatic profile: 1. Serum alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN). 2. Serum aspartate aminotransferase (AST) ≤3 × ULN. 3. Serum bilirubin ≤1.5 × ULN unless elevated due to Gilbert syndrome. 13. Adequate renal function: 1. Estimated creatinine clearance (eClCR) \>30 mL/minute (with eClCR to be calculated by the Cockcroft-Gault formula \[see Appendix 12.2\]), or 2. Measured creatinine clearance \>30 mL/minute (as assessed with a 24-hour urine collection). 14. Adequate coagulation profile: 1. Prothrombin time (PT) ≤1.5 × ULN. 2. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN. 15. Negative viral serology: 1. Negative human immunodeficiency virus (HIV) antibody. 2. Negative hepatitis B surface antigen (HBsAg) and negative hepatitis B core (HBc) antibody or undetectable hepatitis B (HBV) deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) testing. 3. Negative hepatitis C virus (HCV) antibody or negative HCV RNA by quantitative PCR. 16. For female patients of childbearing potential, a negative urine or serum pregnancy test prior to the start of study therapy. 17. For female patients of childbearing potential, willingness to use a highly effective method of contraception from the start of the screening period until ≥3 months after the last dose of cirmtuzumab and ≥1 month after the last dose of ibrutinib, whichever is later. Note: A female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone \[FSH\] levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin \[βHCG\]); or is menopausal (age ≥50 years with amenorrhea for ≥6 months). 18. For male patients who can father a child and are having intercourse with females of childbearing potential who are not using adequate contraception, willingness to use an effective method of contraception from the start of study therapy until ≥3 months after the last dose of cirmtuzumab and ≥3 months after the last dose of ibrutinib, whichever is later and to refrain from sperm donation from the start of study therapy until ≥3 months after administration of the final dose of either of the study drugs. Note: A male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy. 19. In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the patient's cancer. 20. Willingness and ability of the patient to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions. 21. Evidence of a personally signed informed consent indicating that the patient is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation.
Exclusion criteria
1. Known histological transformation to an aggressive lymphoma (ie, Richter transformation). 2. Known central nervous system malignancy. 3. Presence of another cancer with disease manifestations or therapy that could adversely affect subject safety or longevity, create the potential for drug-drug interactions, or compromise the interpretation of study results. 4. Significant cardiovascular disease (eg, myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure; or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive therapy. 5. Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring medication, atrial fibrillation/flutter, left bundle branch block, 2nd-degree atrioventricular (AV) block type II, 3rd-degree AV block, or Grade ≥2 bradycardia. 6. Gastrointestinal disease (eg, gastric or intestinal bypass surgery, pancreatic enzyme insufficiency, malabsorption syndrome, symptomatic inflammatory bowel disease, chronic diarrheal illness, bowel obstruction) that might interfere with drug absorption or with interpretation of gastrointestinal AEs. 7. Contraindication for ibrutinib use because of bleeding diathesis. 8. Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy. Note: Patients with localized fungal infections of skin or nails are not precluded from participation. 9. In patients with prior hematopoietic progenitor cell transplantation, evidence of ongoing graft-versus-host disease (GVHD). 10. Pregnancy or breastfeeding. 11. Major surgery within 4 weeks before the start of study therapy. 12. Prior solid organ transplantation. 13. Prior anti-ROR1 therapy within 12 weeks prior to the start of study therapy. 14. Use of a moderate or strong inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7 days prior to the expected start of ibrutinib therapy. 15. Concurrent participation in another therapeutic or imaging clinical trial. 16. Any illness, medical condition, organ system dysfunction, or social situation, including mental illness or substance abuse, deemed by the investigator to be likely to interfere with a subject's ability to provide informed consent, adversely affect the subject's ability to cooperate and participate in the study, or compromise the interpretation of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response | up to 5 years | Defined as achievement of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL, per standardized criteria \[Hallek 2008\], as recently updated \[Hallek 2018; Cheson 2012\]; and the achievement of a CR or PR for those with MCL or MZL, per based on standardized criteria \[Cheson 2007\] as recently updated \[Cheson 2014\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Up to 5 years | Defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause. PFS was analyzed using Kaplan-Meier Survival Methods. |
| Overall Survival | Up to 5 years | Defined as the interval from the start of study therapy to death from any cause. Overall Survival was analyzed using Kaplan-Meier Survival methods. |
| Duration of Response | Up to 5 years | Defined as the amount of time (months) for achieving of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL; and the amount of time (months) for achieving of a CR or PR for those with MCL. |
| Progression-free Survival (PFS) for Patients With TP53 Mutation Status | Up to 5 years | Defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause, in patients with TP53 mutation status |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MCL Phase 1b, Part 1: 2mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| MCL Phase 1b, Part 1: 4mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| MCL Phase 1b, Part 1: 8mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| MCL Phase 1b, Part 1: 16 mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| MCL Phase 1b, Part 2: 600 mg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 21 |
| CLL Phase 1b, Part 1: 2 mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| CLL Phase 1b, Part 1: 4 mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| CLL Phase 1b, Part 1: 8 mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| CLL Phase 1b, Part 1: 16 mg/kg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| CLL Phase 1b, Part 1: 300 mg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| CLL Phase 1b, Part 1: 600 mg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 3 |
| CLL Phase 1b, Part 2: 600 mg Part 1:
* Cirmtuzumab given by IV infusion every 2 weeks for 5 administrations (Weeks 0, 2, 4, 6, 8) and then every 4 weeks thereafter (Weeks 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 and 52) at a dose of either 2, 4, 8, or 16 mg/kg. After establishment of safety at these dose levels, fixed doses of 300 and 600 mg IV per dose will be examined in patients with CLL/SLL.
* Ibrutinib self-administered orally, QD, continuously starting in Week 4 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL).
Part 2:
* Cirmtuzumab given by IV infusion every 2 weeks for 3 administrations (Weeks 0, 2, 4) and then every 4 weeks thereafter (Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52) using the RDR of cirmtuzumab (600 mg fixed dose IV).
* Ibrutinib self-administered orally QD, continuously starting concurrently with cirmtuzumab in Week 0 at a dose of either 420 mg/day (for patients with CLL/SLL) or at a dose of 560 mg/day (for patients with MCL or MZL). | 16 |
| CLL Phase 2, Part 3: 600 mg Part 3 comprises a Phase 2 open-label, randomized, controlled, 2-arm, parallel-group evaluation of the clinical activity and safety of cirmtuzumab + ibrutinib versus ibrutinib alone. Patients with CLL/SLL will be randomized 2:1 to one of the following 2 regimens in blocks of 6 patients using a pre-generated randomization list:
* Arm A: cirmtuzumab + ibrutinib
* Arm B: ibrutinib alone | 18 |
| CLL Phase 2, Part 3: Ibrutinib Alone Part 3 comprises a Phase 2 open-label, randomized, controlled, 2-arm, parallel-group evaluation of the clinical activity and safety of cirmtuzumab + ibrutinib versus ibrutinib alone. Patients with CLL/SLL will be randomized 2:1 to one of the following 2 regimens in blocks of 6 patients using a pre-generated randomization list:
* Arm A: cirmtuzumab + ibrutinib
* Arm B: ibrutinib alone | 10 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 4 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 5 | 3 |
| Overall Study | Clinical Progression | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Completed 2 years of Treatment | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 8 | 3 |
| Overall Study | COVID Related noncompliance | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Disease Progression | 1 | 2 | 3 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Drug or Study Noncompliance | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Initiation of Alternative Treatment | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Terminated by Sponsor | 2 | 1 | 0 | 1 | 6 | 0 | 0 | 0 | 0 | 0 | 3 | 13 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 4 | 1 | 1 | 0 | 1 | 2 | 0 | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | MCL Phase 1b, Part 1: 2mg/kg | Total | CLL Phase 2, Part 3: Ibrutinib Alone | CLL Phase 2, Part 3: 600 mg | CLL Phase 1b, Part 2: 600 mg | CLL Phase 1b, Part 1: 600 mg | CLL Phase 1b, Part 1: 300 mg | CLL Phase 1b, Part 1: 16 mg/kg | CLL Phase 1b, Part 1: 8 mg/kg | CLL Phase 1b, Part 1: 4 mg/kg | CLL Phase 1b, Part 1: 2 mg/kg | MCL Phase 1b, Part 2: 600 mg | MCL Phase 1b, Part 1: 16 mg/kg | MCL Phase 1b, Part 1: 8mg/kg | MCL Phase 1b, Part 1: 4mg/kg |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 66.3 years STANDARD_DEVIATION 2.1 | 66.0 years STANDARD_DEVIATION 8.9 | 64.7 years STANDARD_DEVIATION 6.7 | 66.2 years STANDARD_DEVIATION 9.2 | 64.3 years STANDARD_DEVIATION 9.5 | 71.3 years STANDARD_DEVIATION 4.9 | 74.0 years STANDARD_DEVIATION 2.7 | 68.7 years STANDARD_DEVIATION 9 | 71.3 years STANDARD_DEVIATION 8.1 | 74.0 years STANDARD_DEVIATION 13.1 | 62.3 years STANDARD_DEVIATION 7.6 | 66.6 years STANDARD_DEVIATION 9.3 | 56.7 years STANDARD_DEVIATION 11.6 | 59.0 years STANDARD_DEVIATION 8.7 | 63.7 years STANDARD_DEVIATION 6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 7 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 78 Participants | 8 Participants | 15 Participants | 15 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 18 Participants | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 3 participants | 95 participants | 10 participants | 18 participants | 16 participants | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 21 participants | 3 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 29 Participants | 7 Participants | 8 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 66 Participants | 3 Participants | 10 Participants | 12 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 0 Participants | 3 Participants | 17 Participants | 3 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 3 | 3 / 3 | 1 / 3 | 7 / 21 | 1 / 3 | 0 / 3 | 1 / 3 | 0 / 3 | 1 / 3 | 0 / 3 | 1 / 16 | 3 / 18 | 1 / 10 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 21 / 21 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 15 / 16 | 18 / 18 | 9 / 10 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 0 / 3 | 2 / 3 | 13 / 21 | 3 / 3 | 1 / 3 | 2 / 3 | 1 / 3 | 2 / 3 | 2 / 3 | 5 / 16 | 9 / 18 | 5 / 10 |
Outcome results
Primary
Overall Response
Defined as achievement of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL, per standardized criteria \[Hallek 2008\], as recently updated \[Hallek 2018; Cheson 2012\]; and the achievement of a CR or PR for those with MCL or MZL, per based on standardized criteria \[Cheson 2007\] as recently updated \[Cheson 2014\].
Time frame: up to 5 years
Population: The efficacy population consists of enrolled subjects who have received at least one dose of either cirmtuzumab or ibrutinib and at least one tumor assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MCL Phase 1b, Part 1: 2mg/kg | Overall Response | 3 Participants |
| MCL Phase 1b, Part 1: 4mg/kg | Overall Response | 3 Participants |
| MCL Phase 1b, Part 1: 8mg/kg | Overall Response | 3 Participants |
| MCL Phase 1b, Part 1: 16 mg/kg | Overall Response | 2 Participants |
| MCL Phase 1b, Part 2: 600 mg | Overall Response | 14 Participants |
| CLL Phase 1b, Part 1: 2 mg/kg | Overall Response | 3 Participants |
| CLL Phase 1b, Part 1: 4 mg/kg | Overall Response | 3 Participants |
| CLL Phase 1b, Part 1: 8 mg/kg | Overall Response | 2 Participants |
| CLL Phase 1b, Part 1: 16 mg/kg | Overall Response | 3 Participants |
| CLL Phase 1b, Part 1: 300 mg | Overall Response | 3 Participants |
| CLL Phase 1b, Part 1: 600 mg | Overall Response | 2 Participants |
| CLL Phase 1b, Part 2: 600mg | Overall Response | 15 Participants |
| CLL Phase 2, Part 3: 600 mg | Overall Response | 15 Participants |
| CLL Phase 2, Part 3: Ibrutinib Alone | Overall Response | 7 Participants |
Secondary
Duration of Response
Defined as the amount of time (months) for achieving of complete response (CR), complete response with incomplete blood count recovery (CRi), partial response (PR), or partial response with lymphocytosis (PR-L) for those with CLL/SLL; and the amount of time (months) for achieving of a CR or PR for those with MCL.
Time frame: Up to 5 years
Population: The subset of the efficacy population achieving Objective Response (ORR). The efficacy population consists of enrolled subjects who have received at least one dose of either cirmtuzumab or ibrutinib and at least one tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MCL Phase 1b, Part 1: 2mg/kg | Duration of Response | NA months |
| MCL Phase 1b, Part 1: 4mg/kg | Duration of Response | NA months |
| MCL Phase 1b, Part 1: 8mg/kg | Duration of Response | 11.9 months |
| MCL Phase 1b, Part 1: 16 mg/kg | Duration of Response | NA months |
| MCL Phase 1b, Part 2: 600 mg | Duration of Response | NA months |
| CLL Phase 1b, Part 1: 2 mg/kg | Duration of Response | 33.5 months |
| CLL Phase 1b, Part 1: 4 mg/kg | Duration of Response | NA months |
| CLL Phase 1b, Part 1: 8 mg/kg | Duration of Response | NA months |
| CLL Phase 1b, Part 1: 16 mg/kg | Duration of Response | NA months |
| CLL Phase 1b, Part 1: 300 mg | Duration of Response | 38.8 months |
| CLL Phase 1b, Part 1: 600 mg | Duration of Response | NA months |
| CLL Phase 1b, Part 2: 600mg | Duration of Response | 40.3 months |
| CLL Phase 2, Part 3: 600 mg | Duration of Response | NA months |
| CLL Phase 2, Part 3: Ibrutinib Alone | Duration of Response | NA months |
Secondary
Overall Survival
Defined as the interval from the start of study therapy to death from any cause. Overall Survival was analyzed using Kaplan-Meier Survival methods.
Time frame: Up to 5 years
Population: The efficacy population consists of enrolled subjects who have received at least one dose of either cirmtuzumab or ibrutinib and at least one tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MCL Phase 1b, Part 1: 2mg/kg | Overall Survival | NA months |
| MCL Phase 1b, Part 1: 4mg/kg | Overall Survival | NA months |
| MCL Phase 1b, Part 1: 8mg/kg | Overall Survival | 22.5 months |
| MCL Phase 1b, Part 1: 16 mg/kg | Overall Survival | NA months |
| MCL Phase 1b, Part 2: 600 mg | Overall Survival | NA months |
| CLL Phase 1b, Part 1: 2 mg/kg | Overall Survival | NA months |
| CLL Phase 1b, Part 1: 4 mg/kg | Overall Survival | NA months |
| CLL Phase 1b, Part 1: 8 mg/kg | Overall Survival | NA months |
| CLL Phase 1b, Part 1: 16 mg/kg | Overall Survival | NA months |
| CLL Phase 1b, Part 1: 300 mg | Overall Survival | NA months |
| CLL Phase 1b, Part 1: 600 mg | Overall Survival | NA months |
| CLL Phase 1b, Part 2: 600mg | Overall Survival | NA months |
| CLL Phase 2, Part 3: 600 mg | Overall Survival | NA months |
| CLL Phase 2, Part 3: Ibrutinib Alone | Overall Survival | NA months |
Secondary
Progression Free Survival (PFS)
Defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause. PFS was analyzed using Kaplan-Meier Survival Methods.
Time frame: Up to 5 years
Population: The efficacy population consists of enrolled subjects who have received at least one dose of either cirmtuzumab or ibrutinib and at least one tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MCL Phase 1b, Part 1: 2mg/kg | Progression Free Survival (PFS) | NA months |
| MCL Phase 1b, Part 1: 4mg/kg | Progression Free Survival (PFS) | NA months |
| MCL Phase 1b, Part 1: 8mg/kg | Progression Free Survival (PFS) | 4.3 months |
| MCL Phase 1b, Part 1: 16 mg/kg | Progression Free Survival (PFS) | NA months |
| MCL Phase 1b, Part 2: 600 mg | Progression Free Survival (PFS) | NA months |
| CLL Phase 1b, Part 1: 2 mg/kg | Progression Free Survival (PFS) | 36.3 months |
| CLL Phase 1b, Part 1: 4 mg/kg | Progression Free Survival (PFS) | NA months |
| CLL Phase 1b, Part 1: 8 mg/kg | Progression Free Survival (PFS) | NA months |
| CLL Phase 1b, Part 1: 16 mg/kg | Progression Free Survival (PFS) | NA months |
| CLL Phase 1b, Part 1: 300 mg | Progression Free Survival (PFS) | NA months |
| CLL Phase 1b, Part 1: 600 mg | Progression Free Survival (PFS) | NA months |
| CLL Phase 1b, Part 2: 600mg | Progression Free Survival (PFS) | NA months |
| CLL Phase 2, Part 3: 600 mg | Progression Free Survival (PFS) | NA months |
| CLL Phase 2, Part 3: Ibrutinib Alone | Progression Free Survival (PFS) | NA months |
Secondary
Progression-free Survival (PFS) for Patients With TP53 Mutation Status
Defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause, in patients with TP53 mutation status
Time frame: Up to 5 years
Population: A subset of the efficacy population with a positive Del(17p) mutation. The efficacy population consists of enrolled subjects who have received at least one dose of either cirmtuzumab or ibrutinib and at least one tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MCL Phase 1b, Part 1: 4mg/kg | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | 16.5 months |
| MCL Phase 1b, Part 1: 8mg/kg | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | 17.3 months |
| MCL Phase 1b, Part 2: 600 mg | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | NA months |
| CLL Phase 1b, Part 1: 300 mg | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | NA months |
| CLL Phase 1b, Part 2: 600mg | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | NA months |
| CLL Phase 2, Part 3: 600 mg | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | NA months |
| CLL Phase 2, Part 3: Ibrutinib Alone | Progression-free Survival (PFS) for Patients With TP53 Mutation Status | NA months |