An Early Phase Study with the Drug LOXO-305 in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Loxo Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

10 Oct 2019 → 23 Dec 2025

Decision date (initial)

2024-06-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-509270-37-00

EudraCT number

2018-003340-24

ClinicalTrials.gov

NCT03740529

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Others, Safety

Phase 1/2 pirtobrutinib monotherapy
Phase 1: To determine the MTD/RP2D of oral pirtobrutinib in patients with previously
treated CLL/SLL and B-cell NHL.
Phase 2: To assess the preliminary antitumor activity of pirtobrutinib based on ORR as
assessed by an IRC. (applicable to CLL/SLL and MCL patients only).
Phase 1b pirtobrutinib in combination:
• To determine the safety of pirtobrutinib in combination with:
Arm A: venetoclax
Arm B: venetoclax + rituximab
• Combination therapy to be performed at selected sites as determined
by the Sponsor.

Secondary objectives 5

1. Phase 1/2 pirtobrutinib monotherapy Phase 1: • To determine the safety profile and tolerability of pirtobrutinib as monotherapy including acute and chronic toxicities. • To characterize the PK properties of pirtobrutinib as monotherapy. • To assess the preliminary antitumor activity of pirtobrutinib as monotherapy based on ORR according to International Workshop Guidelines for CLL/SLL (Hallek et al. 2018) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012) — hereafter referred to as IWCLL 2018 criteria (Appendix E) — and WM (IWWM; Owen et al. 2013, Appendix F); Lugano Treatment Response Criteria for MCL, MZL, and other NHL (Lugano 2014, Cheson et al. 2014, Appendix G); Primary CNS Lymphoma (IWCNSL; Abrey et al. 2005, Appendix H); or other criteria as appropriate to tumor type, as assessed by the Investigator.
2. Phase 1/2 pirtobrutinib monotherapy Phase 2: • To assess, for each Phase 2 cohort, the preliminary antitumor activity of pirtobrutinib by determining: o ORR as assessed by the Investigator o BOR as assessed by the Investigator and IRC ( (applicable to CLL/SLL and MCL patients only)o DOR as assessed by the Investigator and IRC (applicable to CLL/SLL and MCL patients only) o PFS as assessed by the Investigator and IRC (applicable to CLL/SLL and MCL patients only)o OS • To determine the safety profile and tolerability of pirtobrutinib. • To characterize the PK properties of pirtobrutinib. • To determine the association of clinical response categories with: o Symptomatic response: Improvement in cancer-related symptoms among patients with MCL o Functional response: Improvement in physical function among patients with MCL
3. Exploratory Objectives Phase 1/2 pirtobrutinib monotherapy Phase 1 and 2: "• To determine the relationship between PK and drug effects, including efficacy and safety. • To evaluate MRD in select patients during therapy with pirtobrutinib. • To perform exploratory analysis of patient subsets defined by common prognostic markers. • To analyze pretreatment tumor samples for companion diagnostic development. • To characterize BTK and PLCg2 gene mutations, concurrently activated oncogenic pathways, and the pharmacodynamic response to treatment from peripheral blood (e.g., cells and cfDNA), bone marrow, and/or tumor/lymph node biopsies before and during treatment and after PD in select patients receiving pirtobrutinib. • To explore the association of clinical response categories (BOR) with: o Symptomatic response: Improvement in cancer-related symptoms among patients with CLL/SLL and NHL (excluding MCL) tumors. o Functional response: Improvement in physical function among patients with CLL/SLL and NHL (excluding MCL) tumors. • Assess association of PFS with TtW of cancer-related symptoms and physical function for patients by CLL/SLL and NHL tumors. • Explore efficacy, safety, and key patient subgroups with patient reported pain response (using the Worst Pain NRS), role function (using the EORTC QLQ-C30 role functioning subscale), duration of symptomatic response, and duration of functional response.
4. Phase 1b pirtobrutinib in combination: • To characterize the PK properties of pirtobrutinib and venetoclax. • To assess the preliminary antitumor activity of pirtobrutinib in combination based on ORR (according to IWCLL 2018 criteria) as assessed by the Investigator. Additional preliminary antitumor activity assessment will include: o BOR o DOR o PFS"
5. Exploratory Objectives Phase 1b pirtobrutinib in combination: "• To determine the relationship between PK and drug effects, including efficacy and safety. • To evaluate MRD in select patients. • To perform exploratory analysis of patient subsets defined by common prognostic markers. • To characterize BTK and PLCg2 gene mutations, concurrently activated oncogenic pathways, and the pharmacodynamic response to treatment from peripheral blood (e.g., cells and cfDNA), bone marrow and/or tumor/lymph node biopsies before and during treatment and after PD, in select patients.

Conditions and MedDRA coding

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Non-Hodgkin Lymphoma (NHL)"

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Phase 1 dose escalation and expansion and Phase 2: Inclusion criteria / 1: "Phase 1: Histologically confirmed B-cell malignancy (e.g., CLL/SLL, WM, NHL) failed or intolerant to either ≥ 2 prior standard-of-care regimens given in combination or sequentially OR have received 1 prior BTK-containing regimen when a BTK inhibitor is approved as first line therapy.
2. Phase 1 dose escalation and expansion and Phase 2: Inclusion criteria / 2: "Adequate hematologic status, defined as the following on or within 7 days of C1D1 before treatment; see also Exclusion Criterion 8: a. Phase 1 dose escalation and expansion: Absolute neutrophil count (ANC) ≥ 0.75 ×109/L; Phase 1 and Phase 2: the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. b. Phase 1 dose escalation and expansion: Platelet count ≥ 50 × 109/L not requiring transfusion support; Phase 1 and Phase 2: the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. c. Phase 1 dose escalation and expansion: Hemoglobin (Hb) ≥ 8 g/dL not requiring transfusion support or growth factors; Phase 1 and Phase 2: the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. d. Phase 1 and Phase 2: Patient must be responsive to transfusion support. Patients known to be refractory to transfusion support are not eligible.
3. Phase 2 Inclusion criteria Cohort 1 MCL: Confirmed diagnosis of nonblastoid MCL with documentation of either overexpression of cyclin D1 and/or t(11;14) and treated with a prior BTK inhibitor-containing regimen
4. Phase 2 Inclusion criteria "Cohort 2 CLL/SLL: Confirmed diagnosis of CLL/SLL by International Workshop Guidelines for CLL/SLL (IWCLL) 2018 criteria and treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen
5. Phase 2 Inclusion criteria Cohort 3 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 and not previously treated
6. Phase 2 Inclusion criteria Cohort 4 CLL/SLL: Confirmed diagnosis of CLL/SLL by IWCLL 2018 and previously treated, BTK inhibitor naïve"
7. Phase 2 Inclusion criteria "Cohort 5 WM: Confirmed diagnosis of WM with documentation of MYD88 mutation who have received prior therapy with a BTK inhibitor-containing regimen
8. Phase 2 Inclusion criteria "Cohort 6 MZL: Confirmed diagnosis of MZL who have received a prior BTK inhibitor-containing regimen
9. Phase 2 Inclusion criteria "Cohort 7: Defined as CLL/SLL or NHL not otherwise specified in Cohorts 1 through 6, inclusive of CLL/SLL, Richter’s transformation or low-grade NHL with transformation, blastoid MCL, and patients with history of CNS involvement or primary CNS lymphoma. In the event the Sponsor electively closes Cohorts 2 to 4 prior to completion, patients with CLL/SLL who are ineligible to participate in or unable to access late phase studies of pirtobrutinib may be eligible to enroll in this cohort. DLBCL is excluded. MCL without prior BTK inhibitor treatment is excluded. Patients enrolling to Cohort 7 must have received one or more prior therapies or have no available approved therapy with demonstrated clinical benefit with the exception of untreated Richter’s transformation (RT), which is allowed.
10. Phase 2 Inclusion criteria "All patients must have disease requiring treatment. For CLL/SLL patients, indications for treatment are defined by IWCLL. Patients with NHL with measurable disease who will be evaluated by Lugano criteria must have at least 1 site of radiographically assessable disease (i.e., lymph node longest diameter [LDi] > 1.5 cm not necessary for disease assessable by positron emission tomography (PET)/computerized tomography (CT), extra nodal site > 1.0 cm in LDi). Patients with WM must have measurable disease, defined as the presence of serum immunoglobulin M (IgM) with a minimum IgM level of > 2 × the upper limit of normal (ULN) based on local laboratory testing. Patients with nonmeasurable disease are eligible and will be assigned to Cohort 7."
11. Phase 1b pirtobrutinib combinations Inclusion criteria 1/ "Arm A: (venetoclax + pirtobrutinib): Histologically confirmed relapsed/recurrent CLL/SLL in whom venetoclax is appropriate standard salvage treatment; no prior venetoclax is permitted.
12. Phase 1b pirtobrutinib combinations Inclusion criteria 1/ "Arm B: (rituximab + venetoclax + pirtobrutinib [VR-305]): Histologically confirmed relapsed/refractory (r/r) CLL/SLL in whom venetoclax + rituximab is appropriate standard salvage treatment; prior anti-CD20 therapy is allowed; no prior venetoclax is permitted.
13. Phase 1b pirtobrutinib combinations Inclusion criteria 2 "Adequate hematologic status, defined as the following within 7 days of C1D1 before treatment; see also Exclusion Criterion 8: a. ANC ≥ 0.75× 109/L; the patient may enroll if there is documented bone marrow involvement considered to impair hematopoiesis. b. Platelet count ≥ 50 × 109/L not requiring transfusion support; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. c. Hb ≥ 8 g/dL not requiring transfusion support or growth factors; the patient may enroll below this threshold if there is documented bone marrow involvement considered to impair hematopoiesis. d. Patient must be responsive to transfusion support if given for thrombocytopenia or anemia. Patients known to be refractory where increase in platelets to transfusion support is sustained for < 24 hours are not eligible.
14. Inclusion Criteria for All Patients 1 Eastern Cooperative Oncology Group (ECOG) 0 to 2
15. Inclusion Criteria for All Patients 2 At least 18 years of age
16. Inclusion Criteria for All Patients 3 Confirmation of availability of tumor sample obtained after most recent treatment as described in Section 7.4 of the protocol
17. Inclusion Criteria for All Patients 4 "Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) and prothrombin time (PT) or (international normalized ratio [INR]) not greater than 1.5 × ULN
18. Inclusion Criteria for All Patients 5 "Adequate hepatic function, defined as: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN with documented liver metastases b. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver metastases and/or Gilbert’s Disease. If total bilirubin is > 1.5 × ULN, then direct/indirect or conjugated/unconjugated bilirubin tests should be performed and meet the parameter specified. For patients with hemolysis and/or Gilbert’s syndrome, they may be enrolled if unconjugated/indirect bilirubin is < 5 × ULN and conjugated/direct bilirubin is < 3 x ULN."
19. Inclusion Criteria for All Patients 6 "Adequate renal function defined as creatinine clearance of ≥ 30 mL/minute using Cockcroft/Gault Formula: (140 – age) × body weight (kg) × 0.85 (if female) serum creatinine (mg/dL) × 72
20. Inclusion Criteria for All Patients 7 "Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
21. Inclusion Criteria for All Patients 8 "Willingness of men and women of reproductive potential (defined as following menarche and not postmenopausal [and 2 years of nontherapy-induced amenorrhea] or surgically sterile) to observe conventional and highly effective birth control methods with failure rates of < 1% for the duration of treatment and for 1 month following the last dose of study treatment or 12 months following the last dose of rituximab. See Section 4.1 of this protocol for detailed listing of acceptable methods of birth control. Sperm donation is prohibited during the duration of participation on this protocol and for 1 month after the last dose of any study drug. Refer to Section 4.1.

Exclusion criteria 20

1. Investigational agent or anticancer therapy within 5 half-lives or 14 days, whichever is shorter, prior to planned start of specified study therapy except antineoplastic and immunosuppressant monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of pirtobrutinib. In addition, no concurrent systemic anticancer therapy is permitted. a. Continuation of certain standard-of-care anticancer therapies, including hormonal therapy for breast and prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications. Refer to Section 6.4.2 for allowed and Section 6.4.3 for prohibited medications.
2. Major surgery within 4 weeks prior to planned start of specified study therapy
3. "Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment, except for patients receiving radiation to more than 30% of the bone marrow, or receiving whole brain radiotherapy, which must be completed at least 4 weeks prior to the first dose of study treatment
4. Patients requiring therapeutic anticoagulation with warfarin
5. Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 at the time of starting study treatment except for alopecia
6. "History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-T) therapy within the 60 days prior to planned start of specified study therapy or with any of the following: a. Active graft versus host disease (GVHD) b. Cytopenias from incomplete blood cell count recovery post-transplant c. Need for anticytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy d. Ongoing immunosuppressive therapy
7. Known CNS involvement by systemic lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible and enrolled to Phase 2 Cohort 7 if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval.
8. "Active uncontrolled autoimmune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts
9. "Significant cardiovascular disease defined as: a. Unstable angina, or b. History of myocardial infarction within 6 months prior to planned start of pirtobrutinib, or c. Previously documented left ventricular ejection fraction (LVEF) by any method of ≤ 45% in the 12 months prior to planned start of pirtobrutinib; assessment of LVEF via echocardiogram or multigated acquisition (MUGA) scan during Screening should be performed in selected patients as medically indicated, or d. Any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or e. Uncontrolled or symptomatic arrhythmias
10. "Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > 470 msec on all 3 ECGs during Screening. QTcF is calculated using Fridericia’s Formula: QTcF = QT/(RR0.33). a. Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switch to another drug not known to be associated with QTcF prolongation.
11. Patients who experienced a major bleeding event with a BTK inhibitor NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome).
12. "Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection (except for fungal nail infection), or other clinically significant active disease process which, in the opinion of the Investigator and the Sponsor, makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
13. "Patients who have tested positive for human immunodeficiency virus (HIV) are excluded due to potential drug-drug interactions between antiretroviral medications and pirtobrutinib and risk of opportunistic infections with both HIV and irreversible BTK inhibitors. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment.
14. "Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of any of the orally administered study drugs
15. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (refer to Appendix I) and/or strong p-glycoprotein (P-gp) inhibitors (Phase 1b only) (refer to Appendix J)
16. Pregnancy or lactation
17. Active second malignancy unless in remission and with life expectancy > 2 years. Refer to Protocol Exclusion Criteria (Section 4.2) for examples of allowed second malignancies.
18. For patients enrolled to Phase 1b Arm A or B: Patients with prior treatment with venetoclax or other BCL-2 inhibitors
19. Prior treatment with pirtobrutinib
20. "Patients with the following are excluded: • Known hypersensitivity to any component or excipient of pirtobrutinib • For patients enrolled to Phase 1b Arm B, prior significant hypersensitivity, allergy, or anaphylactic reaction to rituximab/biosimilar requiring discontinuation

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Primary Endpoint Phase 1 Monotherapy MTD/RP2D
2. Primary Endpoint Phase 2 Monotherapy "Each Cohort: ORR by appropriate disease-defined criteria and assessed by Independent Review Committee (IRC)
3. Primary Endpoint Phase 1b Combinations "Safety of pirtobrutinib in the specified combinations as described by AEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs

Secondary endpoints 5

1. Ph 1 Monotherapy • AEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs • Plasma concentration of pirtobrutinib and PK parameters including, but not limited to, area under the concentration versus time curve (AUC), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), terminal elimination half-life (T1/2), and degree of accumulation • ORR by Investigator
2. Ph 2 Monotherapy • ORR (by Investigator), best overall response, duration of response, PFS (by Investigator and IRC) • Overall survival • AEs and SAEs, hematology and blood chemistry values, physical examinations, vital signs, and ECGs • Plasma concentration of pirtobrutinib and PK parameters • Symptomatic response: MCL patients • Functional response: MCL patients
3. Exp: • Efficacy and safety based on PK • Rate of MRD (-) • Relationship: prognostic markers, efficacy, and safety • Correlation: molecular testing and diagnostic development • Identity of BTK and PLCg2 gene mutations and activated oncogenic pathways and PD response from blood, bone marrow, tumor/lymph node biopsies • Symptomatic response: CLL/SLL, NHL • Functional response: CLL/SLL, NHL • Time to worsening (TtW) cancer-related symptoms, TtW physical function, pain, role function
4. Phase 1b Combinations "• Plasma concentration of pirtobrutinib, venetoclax, and rituximab when appropriate, and PK parameters, including, but not limited to, AUC, Cmax, Tmax, T1/2, and degree of accumulation • ORR, BOR, DOR, PFS by Investigator
5. Exp. Phase 1b Combinations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Loxo Oncology Inc.

Sponsor organisation

Loxo Oncology Inc.

Address

281 Tresser Boulevard Floor 9th

City

Stamford

Postcode

06901-3238

Country

United States

Scientific contact point

Organisation

Loxo Oncology Inc.

Contact name

Lilly Clinical Trials information desk

Public contact point

Organisation

Loxo Oncology Inc.

Contact name

Lilly Clinical Trials information desk

Third parties 7

Locations

3 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications