| 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) |
|
| 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) |
|
| 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 | 20.1 |
| 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) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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 | 20.0 |
| 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) |
|
| 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 – Dose Escalation:
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-Hodgkin lymphoma (NHL).
Phase 2 – Dose Expansion:
To assess the preliminary anti-tumor activity of LOXO-305 based on ORR as assessed by an Independent Review Committee (IRC). |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1
•To determine safety profile and tolerability of LOXO-305 including acute and chronic toxicities
•To characterize pharmacokinetics (PK) properties of LOXO-305
•To assess preliminary anti-tumor activity of LOXO-305 based on overall response rate (ORR) according to International Workshop Guidelines for CLL/SLL and Waldenstrom Macroglobulinemia, Lugano Treatment Response Criteria for Mantle Cell Lymphoma, Marginal Zone Lymphoma and other NHL, or other criteria as appropriate to tumor type, as assessed by Investigator
Phase 2
•To assess, for each phase 2 cohort, preliminary anti-tumor activity of LOXO-305 by determining
-ORR as assessed by Investigator
-Best overall response (BOR) as assessed by Investigator and IRC
-Duration of response (DOR) as assessed by Investigator and IRC
-Progression-free survival (PFS) as assessed by Investigator and IRC
-Overall survival (OS)
•To determine safety profile and tolerability of LOXO-305
•To characterize PK properties of LOXO-305 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 1
1. Phase 1 dose escalation prior to PK trigger: Able to tolerate potentially subtherapeutic doses of LOXO-305 for the 28-day DLT window in the opinion of Investigator and with documented Sponsor approval
All Patients:
2. Histologically confirmed CLL/SLL or NHL failed or intolerant to standard of care therapies
3. ≥ 2 prior lines of therapy
4. Eastern Cooperative Oncology Group (ECOG) 0-2
5. At least 18 years of age
6. Confirmation of availability of tumor sample obtained after most recent treatment as described in Protocol Section 7.4
7. Adequate hematologic status, defined as the following on C1D1 prior to treatment:
a. Absolute neutrophil count (ANC) ≥ 0.75× 10^9/L and not requiring growth factors; if there is documented bone marrow involvement, growth factors (pegfilgastrim preferred) may be used at any time prior to C1D1 to achieve this ANC threshold
b. Platelet count ≥ 50 × 10^9/L not requiring transfusion support; if there is documented bone marrow involvement, platelet transfusions or growth factors may be used prior to 7 days before C1D1 to achieve this platelet threshold
c. Hemoglobin (Hb) ≥ 8 mg/dL not requiring transfusion support or growth factors; if there is documented bone marrow involvement, growth factors (e.g., epoetin alpha) may be used at any time prior to C1D1 to achieve this Hb threshold
d. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) and prothrombin time (PT) (international normalized ratio [INR]) not greater than 1.5 × upper limit of normal (ULN)
8. Adequate hepatic function, defined as:
a. ALT or AST ≤ 2.5 × the 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
9. 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
10. Ability to swallow tablets and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
11. Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment; this may include barrier methods such as condom or diaphragm with spermicidal gel. For male subjects with a non-pregnant female partner of child-bearing potential and a woman of child-bearing potential one of the following highly effective birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended:
a. Combined estrogen and progestin containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally
b. Progestin-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant
c. Intrauterine device (IUD)
d. Intrauterine hormone-releasing system (IUS)
e. Bilateral tubal occlusion
f. Vasectomized partner
g. Sexual abstinence: considered a highly effective method only if defined as refraining from heterosexual intercourse during an entire period of risk associated with the study treatment. The reliability of sexual abstinence will be evaluated in relation to the duration of the study and to the usual lifestyle of the subject (CTFG 2014).
Birth control methods unacceptable for this clinical trial are:
a. Periodic abstinence (calendar, symptothermal, or post-ovulation methods)
b. Withdrawal (coitus interruptus)
c. Spermicide only
d. Lactational amenorrhea method. |
|
| E.4 | Principal exclusion criteria |
Phase 1 and Phase 2
All Patients:
1. Transformation (e.g., Richter’s transformation, prolymphocytic leukemia, transformed NHL, blastoid lymphoma) prior to planned start of LOXO-305
2. Investigational agent or anticancer therapy within 2 weeks prior to planned start of LOXO-305. In addition, no concurrent investigational therapy is permitted.
a. Continuation of certain standard of care anticancer therapies, including hormonal therapy for localized breast and prostate cancer, is allowed, provided they are not on the list of prohibited concomitant medications. Refer to Protocol Section 6.3.2 for allowed and Section 6.3.3 for prohibited medications.
b. Therapeutic monoclonal antibody treatment must be discontinued a minimum of 4 weeks prior to the first dose of LOXO-305
c. LOXO-305 may be started sooner after prior investigational agent or anticancer therapy if considered by the Investigator to be safe and within the best interest of the patient (e.g., to avoid disease flare) and with documented Sponsor approval.
3. Major surgery within 4 weeks prior to planned start of LOXO-305
4. 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
5. Patients requiring therapeutic anticoagulation
6. Any unresolved toxicities from prior therapy greater than CTCAE (version 5.0) Grade 2 at the time of starting study treatment except for alopecia
7. History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within the last 100 days (180 days before the PK trigger) 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 anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity > Grade 1 from CAR-T therapy
d. ongoing immunosuppressive therapy
8. Known central nervous system (CNS) involvement by lymphoma. Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease may be eligible if a compelling clinical rationale is provided by the Investigator and with documented Sponsor approval
9. Active uncontrolled auto-immune cytopenia (e.g., autoimmune hemolytic anemia [AIHA], idiopathic thrombocytopenic purpura [ITP])
10. Clinically significant, uncontrolled cardiac, cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-305, or 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): QTcF=QT/(RR^0.33).
a. Correction of suspected drug-induced QTcF prolongation can be attempted at the Investigator’s discretion and only if clinically safe to do so.
11. 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.
12. Tested positive for Human Immunodeficiency Virus (HIV) is 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.
13. Clinically significant active malabsorption syndrome or other condition likely to affect GI absorption of the study drug.
14. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (refer to Appendix F) and/or strong P-gp inhibitors (refer to Appendix H).
15. Treatment with PPIs within 7 days of starting LOXO-305 (Appendix G).
a. Refer to Section 6.3.3 for alternatives to PPIs if clinically required.
16. Pregnancy or lactation.
17. Active second malignancy unless in remission with life expectancy > 2 years and with documented Sponsor approval. Examples include:
a. Adequately treated nonmelanomatous skin cancer or lentigo maligna melanoma without current evidence of disease.
b. Adequately treated cervical carcinoma in situ without current evidence of disease.
c. Localized (e.g. lymph node negative) breast cancer treated with curative intent with no evidence of active disease present for more than 3 years and receiving adjuvant hormonal therapy.
d. Localized prostate cancer undergoing active surveillance.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint (Phase 1):
• MTD/RP2D
Primary Endpoint (Phase 2; for each cohort):
• ORR by IRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Endpoint (Phase 1):
• MTD/RP2D will be assessed during Phase 1 of the Trial
Primary Endpoint (Phase 2; for each cohort):
• ORR will be assessed at the end of study Phase 2 |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints (Phase 1):
• 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; 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints (Phase 1):
• 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 |
|
| 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 |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| 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 |
| Sweden |
| Switzerland |
| United Kingdom |
| United States |
|
| 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
|
| Individual patients will continue dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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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