A Study of Oral LOXO-305 in Patients With Previously Treated CLL/SLL or NHL

Sponsor

Loxo Oncology, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03740529

Collaborator

Eli Lilly and Company (Industry)

860

Enrollment

Locations

Arms

58.5

Anticipated Duration (Months)

15.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an open-label, multi-center Phase 1/2 study of oral LOXO-305 (pirtobrutinib) in patients with CLL/SLL and NHL who have failed or are intolerant to standard of care.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia Waldenstrom Macroglobulinemia Mantle Cell Lymphoma Marginal Zone Lymphoma B-cell Lymphoma Small Lymphocytic Lymphoma	Drug: Pirtobrutinib Drug: Venetoclax Drug: Rituximab	Phase 1/Phase 2

Detailed Description

This study includes 3 parts: Phase 1 (pirtobrutinib monotherapy dose escalation and dose expansion), Phase 1b (pirtobrutinib combination therapy dose expansion), and Phase 2 (pirtobrutinib monotherapy dose expansion). In Phase 1, patients will be enrolled using an accelerated titration design. The starting dose of pirtobrutinib in oral tablet form is 25 mg/day (e.g., 25 mg once daily [QD]). Once the MTD and/or RP2D is identified in Phase 1 dose escalation, enrollment will continue to Phase 1 dose expansion and can commence to Phase 1b (Arms A and B). For Phase 2, patients will be enrolled to one of seven Phase 2 dose expansion cohorts depending on tumor histology and prior treatment history. Cycle length will be 28 days.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

860 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Study of Oral LOXO-305 in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) or Non-Hodgkin Lymphoma (NHL)

Actual Study Start Date :

Nov 16, 2018

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Oct 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I Dose Escalation (Pirtobrutinib Monotherapy) Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 3 CLL/SLL patients with no prior therapy.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 1 Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 4 CLL/SLL patients treated with prior therapy, BTK inhibitor naïve.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 2 CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 5 WM patients treated with a prior BTK inhibitor-containing regimen.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) Cohort 6 MZL patients treated with a prior BTK inhibitor-containing regimen.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 2 (Pirtobrutinib Monotherapy) 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 2-4 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 Diffuse large B-cell lymphoma (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, which is allowed.	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727
Experimental: Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727 Drug: Venetoclax Oral Other Names: Venclexta, Venclyxto
Experimental: Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727 Drug: Venetoclax Oral Other Names: Venclexta, Venclyxto Drug: Rituximab IV Other Names: Rituxan MabThera
Experimental: Phase 1 Dose Expansion (Pirtobrutinib Monotherapy) Patients to receive the recommended Phase 2 dose of pirtobrutinib	Drug: Pirtobrutinib Oral Other Names: LOXO-305 LY3527727

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose (MTD) [Up to 24 Months]
Phase I
Recommended dose for further study [Up to 24 Months]
Phase I
To assess the preliminary anti-tumor activity of pirtobrutinib based on ORR as assessed by an Independent Review Committee (IRC). [Up to 24 months]
Phase II
To evaluate the safety of pirtobrutinib in combination with venetoclax (Arm A) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 [Up to 24 Months]
For Phase 1b
To evaluate the safety of pirtobrutinib in combination with venetoclax and rituximab (Arm B) by assessing incidence and severity of treatment-emergent adverse events as determined by CTCAE v5.0 [Up to 24 Months]
For Phase 1b

Secondary Outcome Measures

To determine the safety profile and tolerability of pirtobrutinib including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events. [Up to 24 Months]
Phase I
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points. [Up to 24 Months]
Phase I
To assess the preliminary anti-tumor activity of pirtobrutinib based on overall response rate (ORR) as assessed by investigator. [Up to 24 Months]
Phase I
ORR as assessed by the Investigator. [Up to 24 Months]
Phase II
Best overall response (BOR) as assessed by the Investigator and IRC. [Up to 24 Months]
Phase II
Duration of response (DOR) as assessed by the Investigator and IRC. [Up to 24 Months]
Phase II
Progression free survival (PFS) as assessed by the Investigator and IRC. [Up to 24 Months]
Phase II
Overall survival (OS). [Up to 24 Months]
Phase II
To determine the safety profile and tolerability of pirtobrutinib including acute and chronic toxicities by collecting and evaluating Adverse events and treatment emergent adverse events [Up to 24 Months]
Phase II
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points. [Up to 24 Months]
Phase II
To characterize the pharmacokinetics (PK) properties of pirtobrutinib by collecting and evaluating serum at protocol specified time points. [Up to 24 months]
For Phase 1b
To assess the preliminary anti-tumor activity of pirtobrutinib in combination based on overall response rate (ORR) as assessed by investigator. [Up to 24 months]
For Phase 1b
Symptomatic Response: Change from Baseline in Mantle Cell Lymphoma (MCL)-related symptoms selected from the European Organisation for Research and Treatment of Cancer (EORTC) Item Library [Baseline, End of Treatment (Estimated Up to 24 Months)]
Individual EORTC symptom scores range from 1 (not at all) to 4 (very much) with higher scores representing more severe symptom severity.
Functional Response: Change from Baseline in Physical Functioning as Measured by Physical Functioning Scale from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ) [Baseline, End of Treatment (Estimated Up to 24 Months)]
EORTC physical function item scores range from 1 (not at all) to 4 (very much) with higher scores indicating poorer functioning.The total EORTC physical functioning score ranges from 0-100 where a higher score indicates higher/healthier level of functioning.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed CLL/SLL, WM, or NHL intolerant to either ≥ 2 prior standard of care regimens given in combination or sequentially OR have received 1 prior BTK inhibitor-containing regimen when a BTK inhibitor is approved as first line therapy (Phase 1) OR with prior treatment defined by phase 2 cohort (Phase 2 Patients only).
Adequate hematologic function (Phase 1 and 1b Patients only).
Responsive to transfusion support if given for thrombocytopenia or anemia (Phase 1 and 1b Patients only).
Histologically confirmed relapsed/recurrent CLL in whom venetoclax is appropriate standard salvage treatment; no prior venetoclax is permitted (Phase 1b Arm A Patients only).
Histologically confirmed relapsed/refractory CLL in whom venetoclax + rituximab is appropriate standard salvage treatment; no prior venetoclax is permitted (Phase 1b Arm B Patients only).
Eastern Cooperative Oncology Group (ECOG) 0-2.
Adequate hepatic and renal function.
Ability to receive study drug therapy orally.
Willingness of men and women of reproductive potential (defined as following menarche and not postmenopausal [and 2 years of non-therapy-induced amenorrhea] or surgically sterile) to observe conventional and effective birth control.

Exclusion Criteria:

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.
Major surgery within 4 weeks prior to planned start of specified study therapy.
Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose of study treatment.
Pregnancy or lactation.
Patients requiring therapeutic anticoagulation with warfarin.
Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 or greater at the time of starting study treatment except for alopecia.
History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T-cell (CAR-T) therapy within the past 60 days (180 days before the PK trigger) prior to planned start of specified study therapy.
Known central nervous system (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.
Active uncontrolled auto-immune cytopenia where new therapy introduced or concomitant therapy escalated within the 4 weeks prior to study enrollment is required to maintain adequate blood counts.
Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of pirtobrutinib.
Active uncontrolled systemic bacterial, viral, fungal or parasitic infection.
Patients who have tested positive for human immunodeficiency virus (HIV) are excluded. For patients with unknown HIV status, HIV testing will be performed at Screening and result should be negative for enrollment.
Clinically significant active malabsorption syndrome.
Current treatment with certain strong CYP3A4 inhibitors or inducers and/or strong P-gp inhibitors.
For patients enrolled to phase 1b Arm A or B: Patients with prior treatment with venetoclax or other BCL-2 inhibitors.
Prior treatment with pirtobrutinib.
Active second malignancy unless in remission and with life expectancy > 2 years.
Known hypersensitivity to any component or excipient of pirtobrutinib.
For patients enrolled to phase 1b Arm B: Patients with prior significant hypersensitivity, allergy, or anaphylactic reaction to rituximab/biosimilar requiring discontinuation.
Patients with prior significant hypersensitivity to rituximab requiring discontinuation, prior allergic or anaphylactic reaction to rituximab (Phase 1b Arm B Patients only).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic of Scottsdale	Scottsdale	Arizona	United States	85259
2	Scripps Coastal Medical Center	San Diego	California	United States	92103
3	University of California San Francisco, Medical Center at Paranassus	San Francisco	California	United States	94117
4	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut	United States	06510
5	Mayo Clinic-Jacksonville	Jacksonville	Florida	United States	32224
6	Florida Cancer Specialists ORLANDO/DDU	Lake Mary	Florida	United States	32746
7	Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
8	Florida Cancer Specialists	Sarasota	Florida	United States	34232
9	Emory Clinic	Atlanta	Georgia	United States	30322
10	Northwestern University	Chicago	Illinois	United States	60611
11	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
12	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
13	Mayo Clinic	Rochester	Minnesota	United States	55905-0002
14	University of Nebraska Medical Center	Omaha	Nebraska	United States	68105
15	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
16	Northwell Health	New Hyde Park	New York	United States	11042
17	Columbia University Medical Center	New York	New York	United States	10032
18	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
19	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
20	Durham VA Medical Center	Durham	North Carolina	United States	27705
21	Duke University Medical Center	Durham	North Carolina	United States	27710
22	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
23	Ohio State University Hospital	Columbus	Ohio	United States	43210
24	University of Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19104
25	Sarah Cannon Research Institute SCRI	Nashville	Tennessee	United States	37203
26	Mary Crowley Cancer Research Center	Dallas	Texas	United States	75230
27	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
28	Utah Cancer Specialists	Salt Lake City	Utah	United States	84106
29	Swedish Medical Center	Seattle	Washington	United States	98104
30	Seattle Cancer Care Alliance	Seattle	Washington	United States	98195
31	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
32	Flinders Medical Centre	Bedford Park	South Australia	Australia	5042
33	Peter MacCallum Cancer Centre	Melbourne	Victoria	Australia	3000
34	Linear Clinical Research Limited	Nedlands	Western Australia	Australia	6009
35	Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu	Nantes Cedex 1		France	44093
36	Policlinico S. Orsola Malpighi - Universita di Bologna	Bologna		Italy	40138
37	IRCCS Ospedale San Raffaele	Milano		Italy	20132
38	Nagoya Medical Center	Nagoya	Aichi	Japan	460-0001
39	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
40	Tokai University Hospital	Isehara	Kanagawa	Japan	259-1193
41	Kochi Medical School Hospital	Nankoku	Kochi	Japan	783-8505
42	Tohoku University Hospital	Sendai	Miyagi	Japan	980-8574
43	National Cancer Center Hospital	Chuo Ku	Tokyo	Japan	104-0045
44	Kyushu Cancer Center	Fukuoka		Japan	811-1395
45	Kyoto Furitsu Medical University Hospital	Kyoto		Japan	602-8566
46	Okayama University Hospital	Okayama		Japan	700-8558
47	Kindai University Hospital	Osakasayama-Shi		Japan	589-8511
48	Samsung Medical Center	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	06351
49	Seoul National University Hospital	Seoul		Korea, Republic of	03080
50	Pratia MCM Krakow	Krakow		Poland	30-510
51	Instytut Hermatologii I Transfuzjologii	Warszawa		Poland
52	Karolinska Institutet	Solna	AB	Sweden	171 65
53	Ospedale Regionale di Bellinzona e Valli - Bellinzona	Bellinzona	Ticino	Switzerland	6500
54	St James's University Hospital	Leeds		United Kingdom	LS9 7TF
55	Churchill Hospital	Oxford		United Kingdom	OX3 7LJ
56	Derriford Hospital	Plymouth		United Kingdom	Pl6 8DH