| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Non-Hodgkin Lymphoma (NHL) |
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| E.1.1.1 | Medical condition in easily understood language |
| Malignant Cancers of the Lymphatic System of the Types Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Non-Hodgkin Lymphoma (NHL) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003908 |
| E.1.2 | Term | B-cell small lymphocytic lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029547 |
| E.1.2 | Term | Non-Hodgkin's lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1/2 LOXO-305 monotherapy:
Phase 1
To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of oral LOXO-305 in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-B-cell Hodgkin lymphoma (NHL).
Phase 2
To assess the preliminary anti-tumor activity of LOXO-305 based on ORR as assessed by an Independent Review Committee (IRC).
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| E.2.2 | Secondary objectives of the trial |
Phase 1/2 LOXO-305 monotherapy:
Phase 1
Determine LOXO-305 safety profile and tolerability as monotherapy,
acute and chronic toxicities
Characterize LOXO-305 PK properties as monotherapy
Assess the preliminary anti-tumor activity of LOXO-305 as monotherapy based on ORR (More information in the Protocol)
Phase 2
Assess, for each phase 2 cohort, preliminary anti-tumor activity of LOXO-305 by determining:ORR;Best overall response and IRC;Duration of response and IRC;Progression-free survival as assessed by Investigator and IRC;Overall survival
Determine LOXO-305 safety and tolerability
Characterize LOXO-305 PK properties
Determine the association of clinical response categories (More information in the Protocol)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1/2 LOXO-305 monotherapy: Ph1 dose escalation and expansion
1.Histologically confirmed B-cell malignancy (eg CLL/ SLL, WM, NHL) Failed and 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.Adequate hematologic status, defined as the following on or within 7 days of C1D1 before treatment;see also Exclusion Criterion 8. Please refer to Protocol to complete list.
Phase2:
Sponsor will provide cohort assignment for patient based on diagnosis and prior treatment history information provided during eligibility assessment.Specified cohorts and pretreatment requirements are:
Ch1 MCL:Diagnosis of non-blastoid MCL with documentation of either overexpression of cyclin D1 and/or t(11;14) and treated with a prior BTK inhibitor-containing regimen
Ch2 CLL/SLL:Diagnosis of CLL/SLL by IWCLL 2018 criteria and treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen
Ch3 CLL/SLL:Diagnosis of CLL/SLL by IWCLL 2018 and not previously treated. Patients in UK will not be screened or enrolled to this cohort.
Ch4 CLL/SLL: Diagnosis of CLL/SLL by IWCLL 2018 and previously treated, BTK inhibitor naive
Ch5 WM:Diagnosis of WM with documentation of MYD88 mutation who have received prior therapy with a BTK inhibitor-containing regimen Ch6 MZL:Diagnosis of MZL who have received a prior BTK inhibitor-containing regimen
Cohort 6 MZL: Confirmed diagnosis of MZL who have received a prior BTK inhibitor-containing regimen
Ch7 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 Ch2-4 prior to completion, patients with CLL/SLL who are ineligible to participate in or unable to access late Phase studies of LOXO-305 would remain eligible to enroll in this cohort. In the UK, Cohort 7 may enroll patients who have received prior therapy, who were intolerant of or refused standard first line therapy or patients for whom no approved therapy with demonstrated clinical benefit is available.
All patients must have disease requiring treatment.
All Patients:
1.Eastern Cooperative Oncology Group (ECOG) 0-2
2.At least 18 years of age
3.Confirmation of availability of tumor sample obtained after most recent treatment
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
5.Adequate hepatic function defined as:
a.ALT or AST ≤ 2.5 × ULN or ≤ 5 × ULN with documented liver metastases
b.Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver metastases.If total bilirubin is > 1.5 x 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 x ULN and conjugated/direct bilirubin is < 3 x ULN.
6.Adequate renal function defined as creatinine clearance ≥ 30 mL/minute using Cockcroft/Gault Formula:(140 – age) × body weight (kg) × 0.85 (if female) / serum creatinine (mg/dL) × 72
7.Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
8.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 highly effective birth control methods with failure rates of < 1% for the duration of treatment and for 6 months following the last dose of study treatment; this must include barrier methods such as condom or diaphragm with spermicidal gel. See Section 4.1 of this protocol for detailed listing.Sperm donation is prohibited during the duration of participation on this protocol and for 6 months after the last dose of any study drug
Please refer to Protocol to complete list.
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| E.4 | Principal exclusion criteria |
All Patients:
1.Investigational agent or anticancer therapy within 5 half-lives prior to planned start of specified study therapy except therapeutic monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of LOXO-305.
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
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 or chimeric antigen receptor-modified T cell 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
b.Cytopenias from incomplete blood cell count recovery post-transplant
c.Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy
d.Ongoing immunosuppressive therapy
7.Known central nervous system 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 auto-immune 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 LOXO-305 or
c.Previously documented left ventricular ejection fraction by any method of ≤ 45% in the 12 months prior to planned start of LOXO-305; 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 and mean QTcF > 470 msec on all 3 ECGs, during Screening
QTcF is calculated using Fridericia's Formula (QTcF): 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 or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor
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.
13.Patients who have tested positive for Human Immunodeficiency Virus (HIV) are excluded due to potential drug-drug interactions between anti-retroviral medications and LOXO-305 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 and/or strong p-glycoprotein (P-gp) inhibitors
16.Pregnancy or lactation
17.Active second malignancy unless in remission and with life expectancy > 2 years.
18.Omitted. This criterion has been deleted for UK sites as it only applies to Phase 1b conducted outside the UK.
19.Prior treatment with LOXO-305
20.Patients with known hypersensitivity to any component or excipient of LOXO-305 are excluded.
Please refer to Protocol to complete list.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint (Phase 1 Monotherapy):
• MTD/RP2D
Primary Endpoint (Phase 2 Monotherapy; for each cohort):
• ORR by IRC
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Endpoint (Phase 1 Monotherapy):
• MTD/RP2D will be assessed during Phase 1 of the Trial
Primary Endpoint (Phase 2 Monotherapy; for each cohort):
• ORR will be assessed at the end of study Phase 2 |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints (Phase 1 Monotherapy):
• Adverse events (AEs) and serious adverse events (SAEs), changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs
• Plasma concentration of LOXO-305 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.
Secondary Endpoints (Phase 2 Monotherapy; for each cohort):
• ORR (by Investigator), BOR, DOR, PFS (by Investigator and IRC)
• OS
• AEs and SAEs, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs, and ECGs.
• Plasma concentration of LOXO-305 and PK parameters including, but not limited to AUC, Cmax, Tmax (time to maximum plasma concentration), T1/2, and degree of accumulation.
•Symptomatic Response: Improvement in cancer-related symptoms among patients with Mantle Cell Lymphoma associated with BOR.
•Functional Response: Improvement in physical function among patients with Mantle Cell Lymphoma associated with BOR.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints (Ph1):
• AEs and SAEs: throughout study until incl Safety Follow Up (SFU) period; hematology and blood chemistry, physical examinations and vital signs: Screening, Cycle 1 Days 1/8/15, Day 1 each following Cycle, Intra-Patient Dose Escalation (IPDE) Days 1/8, End of Treatment Visit (EoT), SFU; ECGs: Screening, Cycle 1 Days 1/8, Day 1 Cycles 2-6 then as clinically indicated, IPDE Days 1/8, EoT, SFU
• Plasma concentration of LOXO-305 and PK Parameters: Cycle 1 Days 1/8, Day 1 Cycles 2/4, IPDE Day 8
• ORR (Investigator): Evaluated at end of Phase I
Ph2:
•safety: same as Ph1
•PK see table 7.2 of protocol, C1D8 and C4D1
•ORR : at end of Ph2
•BOR, DOR, PFS, OS etc: at end of Ph2
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase 2 is parallel design, Phase 1 is not |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Poland |
| Singapore |
| Switzerland |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Individual patients will continue dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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