Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Pirtobrutinib · 24 trials · 20 indications
ORR as assessed by independent review committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria
ORR as assessed by independent review committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria
Assessed by blinded independent review committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 Response Criteria
Assessed by blinded independent review committee (IRC) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018
Assessed per Lugano criteria
PFS is defined as the time from the date of randomization to the date of first documentation of progressive disease (PD) or death from any cause, as evaluated by an IRC according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018.
To determine the safety and tolerability of mosunetuzumab in combination with pirtobrutinib.
To determine the efficacy of the combination of mosunetuzumab and pirtobrutinib.
Will report the number of CR and the estimated CR rate with 95% exact binomial confidence interval (CI). Will build logistic regression to evaluate the risk factor association with the endpoint of interest.
Analyses will follow standard methodology by employing Kaplan-Meier (KM) and Cox proportional hazard model methodology. The 1-year PFS rate and 95% CI will be estimated by KM.
To assess the ORR in the study population at Cycle 7.
Overall response rate is defined as the proportion of participants who achieve the best overall response at or before the initiation of subsequent anticancer therapy of CR, CRi, nPR, or PR. ORR will be assessed using International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 response criteria.
Defined by the 2018 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines
VGPR or better response rate is defined as proportion of participants experienced VGPR or complete response (CR) based on modified 6th International Workshop on WM \[IWWM\] criteria (NCCN 2014).
A summary of TEAEs and SAEs regardless of causality, will be reported in the Reported Adverse Events module
DLTs of Pirtobrutinib
Blood Pressure, Pulse Rate, and Body Temperature
Hematology, Clinical Chemistry, Urinalysis, Pregnancy, Hepatitis Serology and Cytomegalovirus (CMV)
ECG QT Interval
Stable platelet response rate is defined as the proportion of participants achieving platelet count of greater than or equal to 50 thousand per microliter (k/μL) and on at least 4 of the 6 consecutive biweekly visits between weeks 14 and 24 in the absence of rescue therapy and prohibited concomitant medication that may impact efficacy
PK: Cmax of Rosuvastatin
PK: AUC(0-inf) of Rosuvastatin
PK: AUC0-24 of Pirtobrutinib
PK: AUC0-t of Pirtobrutinib
PK: AUC0-inf of Pirtobrutinib
PK: %AUCextrap of Pirtobrutinib
PK: CL/F of Pirtobrutinib
PK: t1/2 of Pirtobrutinib
PK: Cmax of Pirtobrutinib
PK: Tmax of Pirtobrutinib
PK: λZ of Pirtobrutinib
PK: Vz/F of Pirtobrutinib
PK: AUC\[0-t\] of Digoxin was reported.
PK: AUC \[tau\] of Digoxin was reported.
PK: CL/F of Digoxin in plasma was reported.
PK: Cmax of Digoxin was reported.
PK: Tmax of Digoxin was reported.
PK: MRT of Digoxin was reported.
PK: Ae of Digoxin in urine was reported. The urine sampling time points from pre-dose through 24 hours post-dose were used to assess this outcome.
PK: Fe of Digoxin was reported. The urine sampling time points from pre-dose through 24 hours post-dose were used to assess this outcome.
PK: CLr of Digoxin in plasma was reported.
PK: AUC\[0-t\] of Pirtobrutinib was reported.
PK: AUCtau of Pirtobrutinib was reported.
PK: CL/F of Pirtobrutinib in plasma was reported.
PK: Cmax of Pirtobrutinib was reported.
PK: Tmax of Pirtobrutinib was reported.
PK: MRT of Pirtobrutinib was reported.
PK: Cmax of pirtobrutinib
PK: t½ of pirtobrutinib
MRT is the average time a drug molecule stays in the body, calculated from the AUC0-inf.
Cmax,u was calculated by multiplying Cmax by Fu (i.e., Cmax\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
AUC0-t,u was calculated by multiplying AUC0-t by Fu (i.e., AUC0-t\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
AUC0-inf,u was calculated by multiplying AUC0-inf by Fu (i.e., AUC0-inf\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
CL/F,u was calculated by multiplying CL/F by Fu (i.e., CL/F\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
Vz/F,u was calculated by multiplying Vz/F by Fu (i.e., Vz/F\*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.
PK: AUC0-24 of pirtobrutinib was reported.
PK: AUC0-t of pirtobrutinib was reported.
PK: AUC0-inf of pirtobrutinib was reported.
PK: Cmax of pirtobrutinib was reported.
PK: Lambda Z of pirtobrutinib was reported.
PK: Vz/F of pirtobrutinib was reported
PK: λZ of pirtobrutinib
PK: λZ of pirtobrutinib
PK: λZ of pirtobrutinib
PK: λZ of pirtobrutinib
The cardiodynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect.
PK: AUC(0-t) of repaglinide was reported.
PK: AUC(0-inf) of repaglinide was reported.
PK: AUC-inf (%extrap) of repaglinide was reported.
PK: Cmax of repaglinide was reported.
PK: Tmax of repaglinide was reported.
PK: Lambda Z of repaglinide was reported.
PK: CL/F of repaglinide was reported.
PK: t½ of repaglinide was reported.
PK: Vz/F of repaglinide was reported.
PK: AUCtau of pirtobrutinib was reported.
PK: Ctrough of pirtobrutinib was reported.
PK: Tmax of pirtobrutinib was reported.
PK: CL/F at steady state of pirtobrutinib was reported.
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: CL/F of midazolam following oral dose administration was reported.
PK: Vz/F of midazolam following oral dose administration was reported.
PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.
PK: CL of midazolam following intravenous dose administration was reported.
PK: Vz of midazolam following intravenous dose administration was reported.
PK: Vss of midazolam following intravenous dose administration was reported.
PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.
TEAE is defined as an adverse event (AE) which starts on or after the first administration of study drug. A serious adverse event is defined as any AE occurring at any dose that results in any of the following outcomes: death; a life-threatening adverse drug experience; inpatient hospitalization or prolongation of existing hospitalization; a persistent or significant disability/incapacity; a congenital anomaly/birth defect; an important medical event that may require medical or surgical intervention to prevent any of the above outcomes.
Phase I
Phase I
Phase II
For Phase 1b
For Phase 1b
| Arm | Type | Description |
|---|---|---|
| Pirtobrutinib Part 1 | EXPERIMENTAL | Participants will receive pirtobrutinib orally. |
| Ibrutinib Part 1 | ACTIVE_COMPARATOR | Participants will receive ibrutinib orally. |
| Pirtobrutinib Part 2 | EXPERIMENTAL | Participants will receive pirtobrutinib orally. |
| Arm A (Pirtobrutinib) | EXPERIMENTAL | Pirtobrutinib administered orally |
| Arm B (BR) | ACTIVE_COMPARATOR | Bendamustine plus rituximab administered intravenously (IV) |
| Arm A (PVR) | EXPERIMENTAL | Fixed duration pirtobrutinib in combination with venetoclax and rituximab |
| Arm B (VR) | ACTIVE_COMPARATOR | Venetoclax with rituximab |
| Arm B (Ibrutinib, Acalabrutinib, or Zanubrutinib) | ACTIVE_COMPARATOR | Investigator's choice (based on local availability) of ibrutinib, acalabrutinib or zanubrutinib orally. Options are limited to those that are available/approved in the specific country. |
| Arm A - Pirtobrutinib | EXPERIMENTAL | Participants received 200 milligrams (mg) of pirtobrutinib administered orally once daily (QD) on Days 1 through 28 of a 28-day cycle. The treatment was continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. |
| Arm B - Idelalisib plus Rituximab or Bendamustine plus Rituximab | ACTIVE_COMPARATOR | Participants received either 150 mg of idelalisib administered twice-daily (BID) orally on Days 1 through 28 of a 28-day cycle in combination with 375 milligram per square meter (mg/m\^2) of rituximab by intravenous (IV) infusion on day 1 of cycle 1, then 4 IV infusions of rituximab 500 mg/m\^2 every 2 weeks (Q2W) and 3 IV infusions of rituximab 500 mg/m\^2 every 4 weeks (Q4W) or 70 mg/m\^2 of bendamustine administered IV on day 1 and 2 of each 28-day cycle from cycles 1 to 6 in combination with 375 mg/m\^2 of rituximab IV on day 1 of cycle 1, then 500 mg/m\^2 of rituximab on day 1 of each 28-day cycle from cycles 2 to 6. |
| Dosing Strategy 1-Mosunetuzumab and Pirtobrutinib | EXPERIMENTAL | Participants receive pirtobrutinib daily on days 1-21 of 21 day cycles. Mosunetuzumab will be administered subcutaneously starting on cycle 2, day 1. If patients have a complete response to treatment, after 9 cycles, they will continue with on pirtobrutinib for a total of 18 cycles. If patients receive a very good partial or minor response, they will continue to receive Mosunetuzumab and Pirtobrutinib for a total of 18 cycles. |
| Dosing Strategy 2- Mosunetuzumab and Pirtobrutinib | EXPERIMENTAL | Participants receive pirtobrutinib daily on days 1-21 of 21 day cycles. Mosunetuzumab will be administered subcutaneously starting on cycle 3, day 1. If patients have a complete response to treatment, after 9 cycles, they will continue with on pirtobrutinib for a total of 19 cycles. If patients receive a very good partial or minor response, they will continue to receive Mosunetuzumab and Pirtobrutinib for a total of 19 cycles. |
| Treatment (pirtobrutinib, mosunetuzumab) | EXPERIMENTAL | Patients receive pirtobrutinib PO QD on 7 days prior to the start of mosunetuzumab (day -7) and continue it until up to 52 weeks. Patients receive mosunetuzumab subcutaneously (SC) or intravenously (IV) on days 1, 8, and 15 of cycle 1 then on day 1 of remaining cycles. Cycles of mosunetuzumab repeat every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity. Patients with a CR after cycle 8 discontinue mosunetuzumab. Patients also undergo blood sample and oral swab and/or rectal swab collection, tissue biopsy, CT, and PET/CT throughout the study. Additionally, patients may undergo bone marrow aspiration and biopsy at screening and after cycle 8. |
| Pirtobrutinib | EXPERIMENTAL | Pirtobrutinib administered orally. |
| Rituximab+Pirtobrutinib, Pirtobrutinib Alone | EXPERIMENTAL | This arm included participants who had a complete response to Rituximab and Pirtobrutinib in Stage 1. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage 2, subjects who experience a complete response will discontinue rituximab and continue treatment with pirtobrutinib only for 6 additional cycles. Participants in this arm will not have Stage 3 treatment. After completing Stage II treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits. |
| Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (6 Cycles) | EXPERIMENTAL | This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Complete Response to continued Rituximab and Pirtobrutinib in Stage 2. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experienced a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experienced a Complete Response will discontinue rituximab and continue treatment with Pirtobrutinib only for 6 additional cycles. After completing Stage III treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits. |
| Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib, Pirtobrutinib Alone (24 Cycles) | EXPERIMENTAL | This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Progressive Disease after continued Rituximab and Pirtobrutinib in Stage 2. In Stage I, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experience a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experience Progressive Disease will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits. |
| Rituximab+Pirtobrutinib, Continuded Rituximab+Pirtobrutinib | EXPERIMENTAL | This arm included participants who had a Partial Response or Stable Disease response to Rituximab and Pirtobrutinib in Stage 1 and a Partial Response or Stable Disease to continued Rituximab and Pirtobrutinib in Stage 2. In Stage I, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). In Stage II, subjects who experience a Partial Response or Stable Disease will continue Rituximab and Pirtobrutinib treatment for 6 additional cycles. In Stage III, subjects who experience a Partial Response or Stable Disease will discontinue rituximab and continue treatment with Pirtobrutinib only until progression or other treatment discontinuation criteria are met. After progression or other treatment discontinuation criteria are met, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits. |
| Rituximab+Pirtobrutinib Only | EXPERIMENTAL | This arm included participants who had Progressive Disease after Rituximab and Pirtobrutinib treatment in Stage 1. In Stage 1, all participants will receive Rituximab and Pirtobrutinib for 6 Cycles (42 days). If participants had Progressive Disease after Stage I, they will not have Stage II or Stage III of treatment. After completing Stage I treatment, subjects will discontinue treatment and proceed to End of Treatment (EOT) and Long-Term Follow-Up (LTFU) visits. |
| Pirtobrutinib Standard Dose (Dose 1)-Part 1 | ACTIVE_COMPARATOR | Pirtobrutinib administered orally. |
| Pirtobrutinib Dose 2-Part 1 | EXPERIMENTAL | Pirtobrutinib administered orally. |
| Pirtobrutinib Dose 3-Part 1 | EXPERIMENTAL | Pirtobrutinib administered orally. |
| Pirtobrutinib Standard Dose-Part 2 | EXPERIMENTAL | Pirtobrutinib administered orally. |
| Pirtobrutinib-Obinutuzumab | EXPERIMENTAL | Eligible participants will receive initial treatment with pirtobrutinib and obinutuzumab for 12 cycles. Participants with progressive chronic lymphocytuc leukemia or small lymphocytic lymphoma during the off-treatment follow-up will receive continuous pirtobrutinib monotherapy. |
| PIRTOBRUTINIB + VENETOCLAX | EXPERIMENTAL | Participants will receive: * Standard of care bone marrow aspirate \& biopsy within 90 days of Cycle 1 Day 1. * Computed Tomography (CT) scan of chest, pelvis \& abdomen within 90 days of Cycle 1 Day 1. * Electrocardiogram at screening. * Cycle 1 * Electrocardiogram. * Day 1-28: Predetermined dose of Pirtobrutinib 1x daily. * Cycle 2 -Day 1-28: Predetermined dose Pirtobrutinib \& Venetoclax 1x daily. Tumor lysis syndrome (TLS) prophylaxis, predetermined dose Allopurinol at least 72 hrs prior to 1st administration of Venetoclax and dose escalation at Day 8 \& Day 15. * Cycles 3-24 * Day 1-28: Predetermined dose of Pirtobrutinib \& Venetoclax 1x daily. * Electrocardiogram: Cycles 3, 6, 9,12,15,18,21,24 * CT scan of chest, pelvis \& abdomen: Cycles 7, 13, End of Treatment if extramedullary disease at baseline unresolved in previous CT scan * Standard of care bone marrow aspirate and biopsy: Cycles 7, 13, End of Treatment * Follow up every 12 wks for 4 yrs. |
| Pirtobrutinib Phase 1 | EXPERIMENTAL | Pirtobrutinib administered orally |
| Pirtobrutinib Phase 2 | EXPERIMENTAL | Pirtobrutinib administered orally |
| Placebo Phase 2 | PLACEBO_COMPARATOR | Placebo administered orally |
| Rosuvastatin + Pirtobrutinib | EXPERIMENTAL | Participants received study intervention through oral administration as follows: * Day 1: 20 milligram (mg) rosuvastatin alone * Day 6: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib * Days 7 to 12: Once daily (QD) doses of 200 mg pirtobrutinib alone * Day 13: 20 mg rosuvastatin co-administered with 200 mg pirtobrutinib * Days 14 to 17: QD doses of 200 mg pirtobrutinib alone. |
| 200 mg Pirtobrutinib (Sequence R/T) | EXPERIMENTAL | Period 1: Participants received a reference formulation (R) of oral pirtobrutinib 200 milligrams (mg) on day 1. Period 2: Participants received a test formulation (T) of oral pirtobrutinib 200 mg on day 8. There was a washout period of 7 days between the doses of pirtobrutinib. |
| 200 mg Pirtobrutinib (Sequence T/R) | EXPERIMENTAL | Period 1: Participants received a test formulation (T) of oral pirtobrutinib 200 mg on day 1. Period 2: Participants received a reference formulation (R) of oral pirtobrutinib 200 mg on day 8. There was a washout period of 7 days between the doses of pirtobrutinib. |
| Digoxin + Pirtobrutinib | EXPERIMENTAL | Participants received oral dose of * 0.25 mg digoxin twice daily (BID) on Day 1 * 0.25 mg digoxin once daily (QD) from Day 2 to Day 7 * 200 mg Pirtobrutinib in combination with 0.25 mg digoxin QD starting from Day 8 to Day 16 |
| Pirtobrutinib (Normal Renal Function) | EXPERIMENTAL | Participants with normal renal function (eGFR \>= 90 mL/min/1.73 m2) received a single dose of Pirtobrutinib 200 milligrams (mg) administered orally on Day 1. |
| Pirtobrutinib (Severe Renal Impairment) | EXPERIMENTAL | Participants with severe renal impairment (eGFR: \< 30 mL/min/1.73 m2) received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. |
| 200 mg Pirtobrutinib: Treatment AB | EXPERIMENTAL | Participants received a single oral dose of 200 milligrams (mg) of pirtobrutinib administered in the morning on Day 1, under fasted conditions (Treatment A) followed by 200 mg pirtobrutinib administered orally in the morning on Day 8, under fed condition (Treatment B). A washout period of 7 days was maintained between Treatments A and B. |
| 200 mg Pirtobrutinib: Treatment BA | EXPERIMENTAL | Participants received a single oral dose of 200 mg pirtobrutinib administered in the morning on Day 1, under fed conditions (Treatment B) followed by 200 mg of pirtobrutinib administered orally in the morning on Day 8, under fasted conditions (Treatment A). A washout period of 7 days was maintained between Treatments A and B. |
| Pirtobrutinib (Normal Hepatic Function) | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 200 milligrams (mg) administered orally on Day 1. |
| Pirtobrutinib (Mild Hepatic Impairment) | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. |
| Pirtobrutinib (Moderate Hepatic Impairment) | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. |
| Pirtobrutinib (Severe Hepatic Impairment) | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1. |
| Placebo | PLACEBO_COMPARATOR | Placebo (matched to Pirtobrutinib) a single oral dose on Day 1, 12 and 23 following a fast of at least 8 hours prior to and 6 hours after dosing. |
| Moxifloxacin | ACTIVE_COMPARATOR | Moxifloxacin a single oral dose on Day 1, 12 and 23 following a fast of at least 8 hours prior to and 6 hours after dosing. |
| Period 1: 0.5 mg Repaglinide | EXPERIMENTAL | Participants received a single oral dose of 0.5 milligrams (mg) repaglinide tablet, in the morning on Day 1. |
| Period 2: 200 mg Pirtobrutinib QD | EXPERIMENTAL | Participants received oral doses of 200 mg pirtobrutinib tablets, once daily (QD) in the morning from Day 2 to Day 11. |
| Period 2: 200 mg Pirtobrutinib QD + 0.5 mg Repaglinide | EXPERIMENTAL | Participants received oral doses of 200 mg pirtobrutinib QD and 0.5 mg repaglinide tablets, in the morning on Day 12. |
| Midazolam (Intravenous [IV] Bolus) | EXPERIMENTAL | A single IV bolus dose of midazolam will be administered in the morning following a 10-hour fast prior to dosing and a 4-hour fast postdose on Day 1 and Day 15. |
| Midazolam Oral | EXPERIMENTAL | A single oral dose of midazolam will be administered in the morning following a 10-hour fast prior to dosing and a 4-hour fast postdose on Day 3 and Day 17. |
| Cohort 1: 300 mg Pirtobrutinib | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 300 milligram (mg) administered orally on Day 1. |
| Cohort 2: 600 mg Pirtobrutinib | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 600 mg administered orally on Day 1. |
| Cohort 3: 800 mg Pirtobrutinib | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 800 mg administered orally on Day 1. |
| Cohort 4: 900 mg Pirtobrutinib | EXPERIMENTAL | Participants received a single dose of Pirtobrutinib 900 mg administered orally on Day 1. |
| Phase I Dose Escalation (Pirtobrutinib Monotherapy) | EXPERIMENTAL | Dose Escalation and determination of MTD; multiple dose levels of pirtobrutinib to be evaluated |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 3 | EXPERIMENTAL | CLL/SLL patients with no prior therapy. |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 1 | EXPERIMENTAL | Non-blastoid MCL patients treated with a prior BTK-inhibitor containing regimen. |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 4 | EXPERIMENTAL | CLL/SLL patients treated with prior therapy, BTK inhibitor naïve. |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 2 | EXPERIMENTAL | CLL/SLL patients treated with 2 or more prior regimens, including a BTK inhibitor-containing regimen. |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 5 | EXPERIMENTAL | WM patients treated with a prior BTK inhibitor-containing regimen. |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 6 | EXPERIMENTAL | MZL patients treated with a prior BTK inhibitor-containing regimen. |
| Phase 2 (Pirtobrutinib Monotherapy) Cohort 7 | EXPERIMENTAL | 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. |
| Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm A | EXPERIMENTAL | Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax |
| Phase 1b Dose Expansion (Pirtobrutinib Combination Therapy) Arm B | EXPERIMENTAL | Relapsed/Refractory CLL will receive the recommended Phase 2 dose of pirtobrutinib in combination with venetoclax and rituximab |
| Phase 1 Dose Expansion (Pirtobrutinib Monotherapy) | EXPERIMENTAL | Patients to receive the recommended Phase 2 dose of pirtobrutinib |
| Name | Type | Description |
|---|---|---|
| Pirtobrutinib | DRUG | Administered orally. |
| Ibrutinib | DRUG | Administered orally. |
| Bendamustine | DRUG | IV |
| Rituximab | DRUG | IV |
| Venetoclax | DRUG | Oral |
| Acalabrutinib | DRUG | Oral |
| Zanubrutinib | DRUG | Oral |
| Idelalisib | DRUG | Oral |
| Mosunetuzumab | DRUG | Administered subcutaneously on day one of applicable cycles. |
| Biospecimen Collection | PROCEDURE | Undergo blood sample and oral swab and/or rectal swab collection |
| Biopsy Procedure | PROCEDURE | Undergo tissue biopsy |
| Computed Tomography | PROCEDURE | Undergo CT and PET/CT |
| Positron Emission Tomography | PROCEDURE | Undergo PET/CT |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Questionnaire Administration | OTHER | Ancillary studies |
| Obinutuzumab | DRUG | Obinutuzumab is given intravenously from Cycle 7 to Cycle 12, for total 6 cycles during initial treatment only. Initial treatment: \- Obinutuzumab intravenous (IV) following the standard schedule from Cycle 6 through Cycle 12 (total 6 cycles: 100 mg on Cycle 6 Day 1, 900 mg on Cycle 6 Day 2, 1000 mg on Cycle 6 Day 8 and Cycle 6 Day 15, 1000 mg on Day 1 of Cycle 7 through Cycle 12). |
| Placebo | DRUG | Administered orally |
| Rosuvastatin | DRUG | Administered Orally. |
| Digoxin | DRUG | Administered Orally. |
| Moxifloxacin | DRUG | Administered orally |
| Repaglinide | DRUG | Administered orally. |
| Midazolam Syrup | DRUG | Administered Orally. |
| Midazolam Solution | DRUG | Administered IV bolus. |
Inclusion Criteria: * Confirmed diagnosis of CLL/SLL requiring therapy per iwCLL 2018 criteria * Part 1 - Known 17p deletion status (wildtype or deleted). Part 2 - Must have deletion of 17p as determined by FISH testing * Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 * Adequate o...