Study of Oral LOXO-338 in Patients With Advanced Blood Cancers
Study Details
Study Description
Brief Summary
The purpose of this study is to find out whether the study drug, LOXO-338, is safe and effective in patients with advanced blood cancer. Patients must have already received standard therapy. The study may last up to approximately 3 years.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
This study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy. If safety and initial evidence of efficacy of LOXO-338 monotherapy are confirmed, part 2 will evaluate the combination of LOXO-338 with the highly selective, noncovalent Bruton's tyrosine kinase (BTK) inhibitor, pirtobrutinib (LOXO-305).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: LOXO-338 (Monotherapy) LOXO-338 administered orally. |
Drug: LOXO-338
Oral
Other Names:
|
| Experimental: LOXO-338 + Pirtobrutinib (Combination) LOXO-338 administered orally in combination with pirtobrutinib |
Drug: LOXO-338
Oral
Other Names:
Drug: Pirtobrutinib
Oral
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Part 1 - To determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of oral LOXO-338 [Cycle 1 (28 Days)]
Measured by the number of patients with dose-limiting toxicities (DLTs)
- Part 1 - To determine the effect of LOXO-338 on response rates [Estimated up to 2 years]
Measured by the appropriate disease specified response criteria as appropriate to tumor type
- Part 2 - To determine the safety and tolerability of LOXO-338 when given in combination with pirtobrutinib [Cycle 2 (28 Days)]
Measured by the number of patients with dose-limiting toxicities (DLTs)
Secondary Outcome Measures
- Part 1 - To characterize the pharmacokinetics (PK) properties of LOXO-338: Area under the plasma concentration versus time curve (AUC) [Predose up to 24 hours postdose]
PK: AUC of LOXO-338
- Part 1 - To characterize the PK properties of LOXO-338: Maximum drug concentration (Cmax) [Predose up to 24 hours postdose]
PK: Cmax of LOXO-338
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on overall response rate (ORR) [Estimated up to 2 years]
ORR
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on progression-free survival (PFS) [Estimated up to 2 years]
PFS
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on time-to-progression (TTP) [Estimated up to 2 years]
TTP
- Part 1 - To assess preliminary antitumor activity of LOXO-338 based on duration of response (DOR) [Estimated up to 2 years]
DOR
- Part 2 - To characterize the pharmacokinetics (PK) properties of LOXO-338 in combination with pirtobrutinib: Area under the plasma concentration versus time curve (AUC) [Predose up to 24 hours postdose]
PK: AUC of LOXO-338 alone and in combination with pirtobrutinib
- Part 2 - To characterize the PK properties of LOXO-338 and in combination with pirtobrutinib: Maximum drug concentration (Cmax) [Predose up to 24 hours postdose]
PK: Cmax of LOXO-338 alone and in combination with pirtobrutinib
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on overall response rate (ORR) [Estimated up to 2 years]
ORR
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on progression-free survival (PFS) [Estimated up to 2 years]
PFS
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on time-to-progression (TTP) [Estimated up to 2 years]
TTP
- Part 2 - To assess preliminary antitumor activity of LOXO-338 alone and in combination with pirtobrutinib based on duration of response (DOR) [Estimated up to 2 years]
DOR
Eligibility Criteria
Criteria
Inclusion Criteria:
-
B-cell malignancy.
-
Patients must have received prior therapy.
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Patients must have an objective indication for therapy.
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Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1.
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Anticipated life expectancy of greater than or equal to (≥) 12 weeks.
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Adequate bone marrow function.
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Adequate hepatic function.
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Creatinine clearance of ≥ 60 milliliters (mL)/minute.
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Ability to swallow tablets.
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Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
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Prior treatment-related adverse events (AEs) must have recovered to grade less than or equal to (≤) 1 or pretreatment baseline, with the exception of alopecia.
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Men with partners of childbearing potential or women of childbearing potential (WOCBP) must agree to use highly effective birth control.
-
WOCBP must not be pregnant.
-
Additional Inclusion Criteria for Patients with AL Amyloidosis
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In Part 1 Dose Expansion, patients with AL amyloidosis are eligible based on prior detection of primary systemic light-chain amyloidosis.
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Must have measurable disease of AL amyloidosis.
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Prior local fluorescence in-situ hybridization (FISH) testing results for t(11;14) are required to be submitted prior to enrollment.
Exclusion Criteria:
-
Prior to identification of an appropriate RP2D (Dose Expansion) of LOXO-338, a history of known, active or suspected:
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Richter's transformation to diffuse large B-cell lymphoma (DLBCL), prolymphocyticleukemia, or Hodgkin lymphoma
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Transformed low grade lymphoma
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Burkitt or Burkitt-like lymphoma
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Diffuse large B-cell lymphoma
-
AL amyloidosis
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Multiple myeloma
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Lymphoblastic lymphoma or leukemia
-
Posttransplant lymphoproliferative disorder
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Known or suspected history of central nervous system (CNS) involvement.
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History of allogeneic or autologous stem cell transplant (SCT) or chimeric antigen receptor-modified T cell (CAR-T) therapy within the past 60 days and with any of the following:
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Active graft versus host disease (GVHD)
-
Cytopenias from incomplete blood cell count recovery post-transplant or CAR-T therapy
-
Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity Grade > 1 from CAR-T therapy
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Ongoing immunosuppressive therapy
-
Known human immunodeficiency virus (HIV) positive, regardless of cluster of differentiation 4 (CD4) count. Unknown or negative status eligible.
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Inability to take necessary uric acid lowering agents (i.e., allopurinol, rasburicase, orfebuxostat).
-
Concurrent anticancer therapy.
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Concurrent treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers that can include antifungals.
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Use of ≥ 20 milligrams (mg) prednisone once a day (QD) or equivalent dose of steroid per day, within 7 days of start of study treatment. Patients may not be on any dose of prednisone intended for antineoplastic use.
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Vaccination with a live vaccine within 28 days prior to start of study therapy.
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Major surgery within four weeks of planned start of study therapy Prolongation of the QT interval corrected by Fridericia's Formula for heart rate (QTcF) greater than (>) 470 milliseconds (msec).
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Clinically significant cardiovascular disease.
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Female patient who is pregnant or lactating.
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Active second malignancy which may preclude assessment of DLT.
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Clinically significant active malabsorption syndrome including surgical resection of small intestine or other condition likely to affect gastrointestinal (GI) absorption of the orally administered study drugs.
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Active hepatitis B or C infection.
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Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) or other clinically significant active disease process.
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Active uncontrolled auto-immune cytopenia.
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Additional Exclusion Criteria for Patients with AL Amyloidosis (Part 1 Dose-Expansion)
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Previous or current diagnosis of symptomatic MM.
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Heart failure that, in the opinion of the Investigator, is on the basis of ischemic heart disease.
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Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension in the absence of volume depletion.
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N-terminal pro hormone natriuretic peptide (NT-proBNP) > 8500 ng/L (or BNP > 700 ng/L if NT-proBNP is not available by local or central testing).
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Additional exclusion criteria for patients enrolled to part 2: LOXO-338 and pirtobrutinib combination
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Prior progression or intolerance to pirtobrutinib.
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Patients requiring therapeutic anticoagulation with warfarin.
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Known hypersensitivity to any component or excipient of pirtobrutinib.
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In patients with history of myocardial infarction or congestive heart failure, documented left ventricular ejection fraction (LVEF) by any method of ≤ 45 percent (%) in the 12 months prior to planned start of study treatment.
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History of uncontrolled or symptomatic arrhythmias including grade ≥ 3 arrhythmia on a prior BTK inhibitor.
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History of major bleeding on a prior BTK inhibitor.
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Current treatment with strong permeability glycoprotein (P-gp) inhibitors.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of California San Francisco, Medical Center at Paranassus | San Francisco | California | United States | 94117 |
| 2 | Mayo Clinic in Florida | Jacksonville | Florida | United States | 32224 |
| 3 | Sylvester Comprehensive Cancer Center | Miami | Florida | United States | 33136 |
| 4 | Indiana Blood & Marrow Transplantation (IBMT) | Indianapolis | Indiana | United States | 46237 |
| 5 | University of Kansas Medical Center | Westwood | Kansas | United States | 66205 |
| 6 | Tufts Medical Center | Boston | Massachusetts | United States | 02111 |
| 7 | Mayo Clinic | Rochester | Minnesota | United States | 55905-0002 |
| 8 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 9 | Swedish Medical Center | Seattle | Washington | United States | 98104 |
| 10 | Medical College of Wisconsin | Milwaukee | Wisconsin | United States | 53226 |
| 11 | L'Institut Universitaire du Cancer de Toulouse Oncopole | Toulouse | Cedex 9 | France | 31100 |
| 12 | Centre Hospitalier Lyon Sud | Pierre-Bénite | Cedex | France | 69495 |
| 13 | CHRU de Montpellier-Hopital St Eloi | Montpellier Cedex 5 | France | 34295 | |
| 14 | Centre Hospitalier Universitaire de Nantes - L' Hopital l'hôtel-Dieu | Nantes | France | 44093 | |
| 15 | Institut Curie | Paris | France | 75248 | |
| 16 | Centre hospitalier universitaire de Haut Leveque | Pessac Cedex | France | 33604 | |
| 17 | IRCCS - AOU di Bologna | Bologna | Italy | 40138 | |
| 18 | Centrum Medyczne Pratia Poznan | Skorzewo | Poznan | Poland | 60 185 |
| 19 | Pratia MCM Krakow | Krakow | Poland | 30-510 |
Sponsors and Collaborators
- Eli Lilly and Company
- Loxo Oncology, Inc.
Investigators
- Study Director: James Pauff, MD; PhD, Loxo Oncology, Inc.
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- LOXO-BCL-20001
- 2021-000060-30
- J3N-OX-JZRA