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4.3.3.4 antiplatelet agents and anticoagulants

Use ibrutinib with caution in subjects requiring anticoagulants or medications that inhibit platelet function. Supplements such as fish oil and vitamin E preparations should be avoided during treatment with ibrutinib. In an in *vitro* platelet function study, inhibitory effects of ibrutinib on collagen-induced platelet aggregation were observed. Bleeding events of any grade, including bruising and petechiae, occurred in subjects treated with ibrutinib. Subjects with congenital bleeding diathesis have not been studied. Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding. For guidance on ibrutinib and the use of anticoagulants during procedures/surgeries, see Section 4.3.5. Subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial fibrillation),
should be monitored closely for signs and symptoms of bleeding and the risks and benefits of continuing ibrutinib treatment should be considered.
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4.3.4 prohibited concomitant medications

Any chemotherapy, anticancer immunotherapy, experimental therapy, or radiotherapy is prohibited while the subject is receiving ibrutinib treatment.  
Corticosteroids for the treatment of the underlying disease are prohibited. Corticosteroids for the treatment of non-cancer related reasons for longer than 14 days and/or at doses > 100 mg of prednisone or its equivalent are prohibited. Use of strong CYP3A inhibitors is contraindicated during venetoclax initiation and dose ramp-up. Subjects may not consume grapefruit or grapefruit products, Seville oranges
(including marmalade containing Seville oranges) or star fruit within the 3-day period prior to the first venetoclax administration and until the last day of treatment is completed due to possible CYP3A mediated metabolic interaction. Erythropoietic growth factors (eg, erythropoietin) and neutrophil growth factors (eg, filgrastim and peg-filgrastim) may be administered per standard practice.
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4.3.5 guidelines for ibrutinib management

Ibrutinib may increase risk of bleeding with invasive procedures or surgery. The following guidance should be applied to the use of ibrutinib in the perioperative period for subjects who require surgical intervention or an invasive procedure while receiving ibrutinib:
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4.3.5.1 minor surgical procedures

For minor procedures (such as a central line placement, needle biopsy, thoracentesis, or paracentesis) ibrutinib should be held for at least 3 days prior to the procedure and should not be restarted for at least 3 days after the procedure. For bone marrow biopsies that are performed while the subject is on ibrutinib, it is not necessary to hold ibrutinib for these procedures.
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4.3.5.2 major surgical procedures

For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be held at least 7 days prior to the intervention (except for emergency procedures) and should be held at least 7 days after the procedure and restarted at the discretion of the investigator when the surgical site is reasonably healed without serosanguinous drainage or the need for drainage tubes.
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4.4 duration of therapy

Upon completion of ibrutinib + venetoclax combination treatment at Week 117, participants will have completed the trial and may transition off-study to receive commercial ibrutinib at the discretion of the investigator. In the absence of treatment delays due to adverse event(s), combination treatment may continue through Week 117, or until one of the following criteria applies:
- Disease progression or relapse
- Unacceptable drug-related adverse event(s)  
- Patient decides to withdraw from the study
- Investigator decision that discontinuation is in the best interests of the patient  
- General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator
- Pregnancy
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4.5 duration of follow-up

Patients will be followed until end of treatment; withdrawal of consent; or death, whichever occurs first. Patients removed from study for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
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4.6 criteria for removal from

Patients will be removed from study treatment when any of the criteria listed in Section 4.4 applies. The reason for treatment termination and the date the patient was removed must be documented in the Case Report Form (CRF).
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4.6.2 removal from study

Withdrawal from the study including termination of all follow-up will occur if:
- The subject is lost to follow-up following reasonable effort from study staff to contact the subject
- The subject withdraws consent for follow-up observation  
- The subject dies
- The study is terminated Documentation of the reason for withdrawal and withdrawal of full (treatment and all further contact) or partial (withdrawal of consent to treatment but not to follow-up visits) consent will be must be documented in the Case Report Form (CRF).
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4.7 study risk information

Risks of the study drugs are described within the venetoclax and ibrutinib Investigator's Brochures and FDA-approved labeling for each.
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4.8 risk mitigation

Risk mitigation will include safety assessments during clinic visits at weeks 1; 5; and 9 (ibrutinib treatment only); then weekly for 4 weeks during the venetoclax dose ramp-up; then, during the venetoclax + ibrutinib stage, every 4 weeks through Week 30; then at Week 38, Week 62, and every 12 weeks thereafter. Safety assessments will include hematology; serum chemistry; physical exam with vital signs, weight, and ECOG performance status; and subject interviews for adverse events and concomitant medications.
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5 study drug information 5.1

Study drug venetoclax is approved by the US Food and Drug Administration (FDA) as Venclexta. The approved uses of venetoclax are described at Section 2.2.1 Venetoclax.
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5.1.2 formulation

The venetoclax tablets will be packaged in high-density polyethylene (HDPE) plastic bottles or blister packs to accommodate the study design. Each container will be labeled per local regulatory requirements. Tablets are formulated with 10 mg, 50 mg and 100 mg doses. Blister Packs will contain study drug for one week plus one extra day. Subjects will be instructed to take the extra day's dose (noted with an "X" on the Blister Pack) only if directed by the investigator.
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5.1.3 study cohorts / arms

This is a single-arm, open label study. All participants will receive ibrutinib for 8 weeks, then begin dose-escalation with venetoclax as described elsewhere in the protocol.
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5.1.4 mechanism of action

Venetoclax is a novel, orally available small molecule Bcl-2 family protein inhibitor that binds with > 500-fold higher affinity (Ki < 0.010 nM) to Bcl-2 and with lower affinity to other Bcl-2 family proteins Bcl-XL (Ki - 48 nM) and Bcl-w (Ki - 245 nM). Overexpression of anti-apoptotic Bcl-2 family proteins is associated with increased resistance to chemotherapy, and antagonism of the action of these proteins might enhance response to such therapy and overcome resistance.  
Anti-apoptotic Bcl-2 family members are associated with tumor initiation, disease progression, and drug resistance, making them compelling targets for antitumor therapy.  
In vitro, venetoclax demonstrated broad cell killing activity against a panel of lymphoma and leukemia cells including B-cell follicular lymphomas (FLs), mantle cell lymphomas (MCLs),
diffuse large B-cell lymphomas (DLBCLs), and acute myeloid leukemias (AMLs). Venetoclax was especially potent against cell lines expressing high levels of Bcl-2. Leukemia and lymphoma cell lines bearing the t(14;18) translocation were significantly more sensitive to venetoclax than non-mutated cell lines.
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5.1.5 non-clinical and clinical pharmacokinetics

In vitro studies have shown that venetoclax is metabolized primarily by CYP3A4; thus, co-administration of venetoclax with drugs that inhibit CYP3A4 (such as ketoconazole) is predicted to cause a significant increase in the exposure of venetoclax and will be undertaken with caution. In a phase-I dose-escalation trial in patients with relapsed/refractory NHL, after a single dose administration with a high-fat meal, venetoclax reached Cmax at approximately 7 hours with a terminal half-life of about 15 hours. Food increased venetoclax exposure by approximately 3-fold.
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5.1.6 summaries of non-clinical pharmacology

Venetoclax inhibited subcutaneous murine xenograft growth of human tumor cell lines derived from acute lymphoblastic leukemia (ALL) and Non-Hodgkin's Lymphoma (NHL). The drug was also active in a model of disseminated ALL.
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5.1.6.1 non-clinical toxicology studies

The nonclinical toxicology of venetoclax has been evaluated in repeated-dose studies in mice and dogs with up to 4 weeks of once daily oral dosing (and with 4-week recovery periods) and in dogs with 2 weeks of dosing (18-week recovery period); safety pharmacology studies
(cardiovascular, neurofunctional, and pulmonary); and in genetic toxicity tests (Ames and in vitro chromosome aberrations assays). The primary toxicities associated with venetoclax administration included effects on the hematologic system (lymphocytes and red blood cell parameters) in mice and dogs and on the male dog reproductive system. There was no evidence of genotoxicity of venetoclax. A severely toxic dose (STD10) was not identified in mice up to and including the top dose of 600 mg/kg/day (overall mean AUC0-24 = 91.5 μg•hr/mL and Cmax = 7.2 μg/mL). In dogs, the highest non-severely toxic dose (HNSTD) was 150 mg/kg/day, but due to overlapping exposures between the mid and high doses, the HNSTD was defined as the mid dose of 50 mg/kg/day (overall mean AUC0-24 = 472 μg•hr/mL and Cmax = 27.4 μg/mL). Venetoclax causes decreases in circulating lymphocytes and lymphocytes in lymphoid tissue. After 4 weeks of dosing, the lymphocyte effects were reversible or partially reversible in the mouse but generally were less reversible in the dog at the end of a 4-week recovery period.  
However, in a 2-week dog study focused on lymphocyte recovery over an extended (18-week) period, reversibility of lymphocyte effects was demonstrated. Immunophenotyping was used to assess changes in peripheral blood lymphocyte subsets (ie, mature T-cells, helper T-cells, cytotoxic T-cells, and mature B-cells). At the end of the 18-week recovery period, both total and lymphocyte subset counts returned to within range of baseline and control values, and all effects on lymphoid tissue reversed. The venetoclax–related decreases in lymphocytes in blood and lymphoid tissues are considered pharmacologically mediated and non-adverse.  
Additional hematological effects of venetoclax treatment included reversible decreases in red blood cell parameters (primarily, hematocrit and hemoglobin concentration) in mice and dogs.  
The decreases in red cell parameters were adverse only at the high dose levels in the 4-week studies (ie, at 600 mg/kg/day in mice and at 150 mg/kg/day in dogs, but all red cell parameters were reversible at the end of a 4-week recovery period. Effects on both lymphocytes and red cell mass are readily monitored in subjects. Dogs at the high dose of 150 mg/kg/day in the 4-week study had clinical signs of itching and swelling of the skin on the ears, head (cranial area), and forepaws and/or hindpaws. Most of the animals (8 of 10 dogs) were affected. The clinical signs were mild to moderate in severity, transient and sporadic in occurrence, and were absent during the recovery period. The swelling reactions were observed after the first dose in 3 dogs, and therefore not consistent with drug-induced immediate (IgE-mediated, Type I) hypersensitivity; however, other immune-mediated mechanisms could be involved. Although the basis for the swelling reactions was not established, there were no signs of anaphylaxis. Any occurrences of swelling reactions in patients can be monitored and treated. In an ongoing 9-month chronic toxicity study of dogs with venetoclax, hypopigmented (white) facial hair was observed after approximately 3 months of dosing (ongoing study Abbvie R&D/12/384). The finding was limited to the mid and high doses (6 and 20 mg/kg/day), and was observed in both males and females. Evidence from Bcl-2 knockout mouse (bcl-2-/-) studies indicates that hair hypopigmentation is consistent with the pharmacological effect of Bcl-2 functional loss, and occurs due to loss of hair follicle melanocytes dependent on Bcl-2 for survival.  
28 A dedicated physical examination of the skin and extensive ophthalmic examinations determined that pigmentation of the skin and in the eye (particularly in the iris and fundus)
appears unaffected. The potential for development of white (hypopigmented) hair in humans is unknown. Venetoclax was tested in a battery of safety pharmacology assays and produced no effects in central nervous system/neurobehavioral, or respiratory studies in mice at oral doses up to 600 mg/kg. In an anesthetized dog cardiovascular model given intravenous doses of venetoclax, mild reductions in myocardial contractility (maximum rate of rise of left ventricular pressure [dP/dtmax]: –6% to –13%) and cardiac output (–11% to –19%) were observed at plasma concentrations of ≥ 16 μg/mL and ≥ 32 μg/mL, respectively. However, no effect on blood pressure, heart rate, or electrocardiogram (ECG) parameters were observed relative to baseline or controls in either the anesthetized dog study or in the conscious dog cardiovascular study using telemeterized animals at maximum drug concentrations of 46 μg/mL and 16 μg/mL, respectively.  
Nonclinical safety pharmacology and toxicology evaluations of venetoclax, as well as nonclinical and human studies of related anti-apoptotic Bcl-2 family protein inhibitors, suggest potential mechanism-based toxicities may include lymphopenia and neutropenia,29 signs of tumor lysis, reduction in red cell mass, decreased spermatogenesis, skin swelling, and hair hypopigmentation. Thrombocytopenia has not been observed in toxicology studies in mice and dogs. These findings are consistent with venetoclax as a Bcl-2 specific (Bcl-XL sparing) inhibitor. Consequently, thrombocytopenia is not expected to be a dose-limiting toxicity (DLT) clinically. A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be found in the current version of the Investigator's Brochure.
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5.1.6.2 carcinogenesis mutagenesis impairment of

Male dog reproductive effects consisted of markedly reduced numbers of spermatogonia in the testes at all venetoclax dose levels after 4 weeks of dosing, with progression to severe decreases in the numbers of all germ cells in testes during the 4-week recovery period. Male mice did not have testicular changes associated with venetoclax administration. The translatability of the testicular findings in dogs to humans is unknown, but this change may be related to venetoclax pharmacology, as one or more members of the Bcl-2 family of proteins play a role in spermatogenesis.30-32 In view of the potential treatment benefits of venetoclax, this finding is anticipated not to impact the treatment of subjects with advanced hematologic malignancies.
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5.1.7 summaries of clinical studies

As of 28 November 2015, data available in the AbbVie and Genentech/Roche clinical databases include a total of 1662 subjects who have been exposed to at least 1 dose of venetoclax in the oncology and immunology development programs. A total of 1498 oncology subjects have data available in AbbVie and Genentech/Roche studies as of 28 November 2015. Of these 1498, 935 subjects had CLL/small lymphocytic leukemia (SLL), 346 subjects had NHL, 115 subjects had MM, 102 had AML. An additional 66 subjects were healthy volunteers. A total of 564 oncology subjects received the drug as monotherapy, 933 received the drug in combination with other therapies, and 1 subject received venetoclax as a single dose in a DDI study and did not re-enroll into a subsequent monotherapy study. Additionally, 98 subjects were exposed to at least 1 dose of venetoclax in the AbbVie immunology study, Study M13-093, as of 28 November 2015.  
Preliminary efficacy results are available for subjects with CLL/SLL, NHL, MM, and AML as listed below. Preliminary data indicate that venetoclax continues to show promising efficacy in oncology subject populations.  
- In venetoclax monotherapy Study M12-175 (as of 25 August 2015), the overall remission rate (ORR; investigator-assessed) in Arm A (R/R CLL/SLL) in the Dose-Escalation and Safety Expansion Cohorts was 79%.33 The ORR (investigator-assessed) in Arm B (R/R
NHL) was 38% for FL subjects and 18% for DLBCL subjects (Dose-Escalation and Safety Expansion Cohorts).  
- In venetoclax monotherapy Study M13-982 (as of 30 April 2015), the ORR
(IRC-assessed) for R/R CLL subjects was 74%.  
- In venetoclax monotherapy Study M14-032 (as of 25 August 2015), the ORR for R/R
CLL subjects in Arm A (ibrutinib-resistant) was 42% and in Arm B (idelalisib-resistant) was 29%.  
- In Study M13-365 (as of 28 October 2015) the ORR for R/R CLL/SLL subjects treated with venetoclax + rituximab was 86%.  
- In Study M12-630 (as of 17 September 2015), the ORR for R/R NHL subjects treated with venetoclax + BR was 67%.  
- In Study M13-367 (as of 17 September 2015), the ORR for R/R MM subjects treated with venetoclax was 24% in t(11;14)-positive subjects and 4% in t(11;14)-negative subjects.  
- In Study M12-901 (as of 17 September 2015), the ORR for R/R MM subjects treated with venetoclax and bortezomib/dexamethasone was 100% in bortezomib-naïve subjects, 71% in bortezomib-sensitive subjects, and 17% in bortezomib-refractory subjects.  
- In Study M14-212 (as of 07 October 2014), the ORR for AML subjects treated with venetoclax monotherapy was 19%.  
- In Study M14-358 (as of 19 September 2015), the ORR for AML subjects was 77%. - In Study M14-387 (as of 28 November 2015), the ORR for AML subjects was 44%.
For the most comprehensive clinical information regarding venetoclax, refer to the current version of the Investigator's Brochure.
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5.1.8 major route of elimination

Following oral administration in mouse, rat, dog, and human, venetoclax and its metabolites were cleared primarily via biliary excretion and fecal elimination, with minimal renal clearance.
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5.1.9 safety profile

The preliminary clinical data of venetoclax monotherapy in subjects with CLL/SLL, MCL and NHL have shown a favorable benefit to risk ratio in Study M12-175. As of 3 February 2014, a total of 153 subjects have been enrolled in Study M12-175, and had data available for the study
(95 in Arm A and 58 in Arm B). The most common adverse events in Arm A (CLL/SLL subjects)
were diarrhea (38.9%), neutropenia (37.9%), nausea (34.7%), upper respiratory tract infection (30.5%), fatigue (27.4%), and cough (20.0%). The most common adverse events in Arm B (NHL subjects) were nausea (32.8%), diarrhea (24.1%), and fatigue and upper respiratory tract infection (20.7% each). The most common adverse events reported for all subjects in the study were nausea (34.0%), diarrhea (33.3%), neutropenia (29.4%), upper respiratory tract infection (26.8%), and fatigue (24.8%). The most common events Grade 3 or above reported in Arm A (CLL/SLL
subjects) were neutropenia (34.7%) and anemia (10.5%), and in Arm B (NHL subjects) were anemia (15.5%) and neutropenia (10.3%). Overall, Grade 3 or 4 adverse events reported in
> 5% of patients were anemia, neutropenia, febrile neutropenia, thrombocytopenia, hyperglycemia, and tumor lysis syndrome (TLS). These adverse events were mostly consistent with complications commonly observed in heavily pretreated patients with R/R CLL/SLL. Febrile neutropenia was the most common serious adverse event observed with venetoclax monotherapy treatment (7.0%); all events resolved on supportive treatment, and none resulted in discontinuation from the study. The only other serious adverse event reported in more than 2 subjects was TLS (11.0%) for venetoclax as a single agent. A comprehensive safety review identified risk factors for developing TLS from Study M12-175 as well as Study M13-365 (venetoclax in combination with rituximab), resulting in implementation of a modified dose-escalation regimen and revised TLS risk management procedures in ongoing studies in various hematologic malignancies.
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5.1.9.1 tumor lysis syndrome (tls)

TLS is considered an important identified risk and is predominantly seen in the CLL population with high tumor burden. Primary CLL cells are essentially dependent on Bcl-2 for survival and are exquisitely sensitive to the Bcl-2 specific inhibitor venetoclax, and the on-target pharmacological effect can cause rapid reduction in size of tumor (debulk) and may pose a risk of TLS. The management of the risk of TLS with venetoclax has evolved over time. In Study M12-175 (June 2011), substantial anti-tumor activity was observed in the first 3 subjects with CLL
following a single dose of venetoclax of 100 to 200 mg. Within 24 hours, reductions in palpable lymphadenopathy were observed in all 3 subjects and dramatic reductions in lymphocyte count (> 95%) were observed in the 2 subjects with pretreatment lymphocytosis. This rapid response resulted in TLS in all 3 subjects, mainly characterized by increases in potassium, phosphate, and LDH levels which resolved without clinical complications in all 3 subjects. Subsequently, the initial venetoclax dose for CLL subjects was reduced to 50 mg, and 2 to 3 weekly ramp-up steps were introduced to reach the final cohort dose. In addition, in all subjects, intensified monitoring and standard TLS prophylaxis measures were mandated, including protocol-specified laboratory tests, hydration, and treatment to prevent hyperuricemia. In the subsequent cohorts, a CLL subject developed TLS and acute renal failure requiring dialysis. This subject presented with elevated potassium and ECG changes indicating possible myocardial infarction. Subsequently, a cardiac catheterization was performed. The acute renal failure may have also been due to the radiographic dye in the setting of TLS. Hospitalization of CLL/SLL subjects with the first dose of venetoclax became mandatory following the report of this serious adverse event.  
In December 2012, 2 fatal adverse events in the setting of TLS were reported in subjects with CLL/SLL. The first death (in Study M13-365) occurred within 24 hours after the subject received his first dose of 50 mg venetoclax. The second death (in Study M12-175) occurred within 48 hours after the subject had escalated to the final dose of 1200 mg/daily of venetoclax, the highest dose administered in the venetoclax program to date. Following the report of 2 fatal adverse events in the setting of TLS in December 2012, the clinical program was halted and a comprehensive review of all safety data available from studies with venetoclax revealed:  
- The highest risk period for developing TLS is at initiation of venetoclax. The risk is reduced as the tumor burden decreases.  
- Subjects with TLS appeared to have had a higher venetoclax exposure than subjects without TLS. To reduce the initial exposure for all subjects to that of subjects not experiencing TLS (Cmax ≤ 0.23 μg/mL), trial simulation data indicated that subjects should receive 20 mg as a starting dose.  
- Bulky lymph nodes ≥ 5 cm and elevated screening ALC ≥ 38.9 × 109/L were identified as risk factors for TLS following administration of venetoclax. Screening CrCl < 80 mL/min was also identified as a contributing factor. These TLS risk factors are not unique to venetoclax and have been previously identified in the literature.  
- The 2 subjects who had fatal CTLS (Subject 167 in Study M12-175, and Subject 5503 in Study M13-365) had nodes greater than or approximately equal to 10 cm in size.
Based on the analyses and discussion with regulatory authorities, the clinical program was reinitiated in May 2013 with a modified venetoclax dosing regimen and enhanced TLS
prophylaxis and monitoring measures: frequent blood draws, uric acid reducing agents
≥ 72 hours prior to first dose, and site education plan. Repeat analysis in January 2014 performed to evaluate the effectiveness of revised measures indicated a marked reduction in severity and frequency of TLS when compared to the previous analysis. None of the subjects experienced any serious (including fatal) or non-serious event of CTLS or laboratory TLS
(LTLS) or had study treatment discontinued because of TLS. The revised dosing regimen, which includes a more gradual increase in dose, likely led to gradual debulking of the tumor and played a key role in mitigating the risk. Based on the results of this interim analysis, following revisions were made in May 2014:  
- All subjects starting venetoclax treatment at 20 mg QD for 1 week followed by gradual weekly titration up to the 400 mg QD dose.  
- More personalized approach for prophylaxis and monitoring measures, where subjects with low and medium risk for TLS could receive venetoclax on an out-patient basis with post-dose laboratory monitoring at 8 and 24 hours. Subjects at high risk for TLS were hospitalized for their initial dose at 20 mg and 50 mg and then managed on an out-patient basis.  
- Oral uricosurics starting 72 hours prior and oral hydration starting 48 hours prior to starting venetoclax; additional IV fluids for high and medium risk subjects. Rasburicase is recommended for subjects at high risk, especially those with high baseline values.
E  
- Reassessment of tumor burden based on current ALC followed by less intensive prophylaxis and monitoring was allowed, based on the investigator's discretion.
From May 2014 to 25 August 2015, a total of 105 subjects have received venetoclax following the above measures in monotherapy CLL Study M13-982 (safety expansion cohort) and Study M14-032. Adverse events of TLS are reported in 4/105 (3.8%) subjects, with no events of CTLS.  
Hyperkalemia (or blood potassium increased) was the most common laboratory adverse event relevant to TLS, and was reported in 17/105 (16.2%; one Grade 3 event) of subjects. Hyperphosphatemia was reported in 15/105 (14.3%, 22 Grade 3 events) subjects; hypocalcaemia in 10/105 (9.5%) subjects, and hyperuricemia in 9/105 (8.6%) subjects. All adverse events related to clinical chemistries resolved with standard electrolyte management without any clinical consequences.  
Current recommendations for TLS prophylaxis and monitoring in CLL are summarized in Section 4.3.1.
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5.1.10 rationale for the starting

Daily oral dosing of venetoclax at 400 mg has been well tolerated in CLL patients previously as mono-agent therapy; higher doses have also been tested in other malignancies though without significantly increased efficacy in CLL/SLL. Implementation of intra-patient dose-escalation with venetoclax, pre-treatment TLS risk categorization, and enhanced prophylactic guidance and monitoring for TLS has eliminated the significant tumor lysis that was previously seen with initiation of venetoclax therapy at higher doses. A similar use of intra-patient dose-escalation for venetoclax in this study will allow rapid identification of the maximal tolerable dose while maintaining high sensitivity for adverse events and dose-limiting toxicities.
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5.1.11 maximum allowable dose/ overdose

The maximum allowed dose of venetoclax in this study is 400 mg. Any dose of study drug more than that specified in this protocol is considered an overdose.  
Signs and symptoms of an overdose that meet any Serious Adverse Event criterion must be reported as a Serious Adverse Event in the appropriate time frame and documented as clinical sequelae to an overdose. There is no specific antidote for venetoclax. In the event of an overdose, subjects should be closely monitored and given appropriate supportive treatment. Refer to Section 7 for further information regarding AE reporting.
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5.1.12 treatment duration

Treatment duration of venetoclax for this study is 2 years in combination with ibrutinib.
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5.2 study drug ibrutinib 5.2.1

Study drug ibrutinib is approved by the US Food and Drug Administration (FDA) as Imbruvica. The approved uses of ibrutinib are described at Section 2.2.2 Ibrutinib.
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5.2.2 formulation

Ibrutinib capsules are provided as a hard gelatin capsule containing 140 mg of ibrutinib. All formulation excipients are compendial and are commonly used in oral formulations. Refer to the ibrutinib Investigator's Brochure for a list of excipients.  
The ibrutinib capsules will be packaged in opaque high-density polyethylene plastic bottles with labels bearing the appropriate label text as required by governing regulatory agencies. All study drug will be dispensed in child-resistant packaging. Study drug labels will contain information to meet the applicable regulatory requirements. The first dose of ibrutinib will be delivered in the clinic on Day 1, after which subsequent dosing is typically on an outpatient basis. Unused ibrutinib dispensed during previous visits must be returned to the site and drug accountability records updated at each visit. Refer to the pharmacy manual/site investigational product manual for additional guidance on study drug storage, preparation and handling.
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5.2.3 study cohorts

All study participants will receive ibrutinib daily starting at Week 1 Day 1 at the FDA-approved dose for CLL/SLL.
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5.2.4 mechanism of action

Ibrutinib was designed as a selective and covalent inhibitor of Bruton's tyrosine kinase (BTK).34 In vitro, ibrutinib is a potent inhibitor of BTK activity (IC50 = 0.39 nM). The irreversible binding of ibrutinib to cysteine-481 in the active site of BTK results in sustained inhibition of BTK catalytic activity and enhanced selectivity over other kinases that do not contain a cysteine at this position. When added directly to human whole blood, ibrutinib inhibits signal transduction from the B-cell receptor and blocks primary B-cell activation (IC50 = 80 nM) as assayed by anti-IgM
stimulation followed by CD69 expression.  
35 For more detailed and comprehensive information regarding pharmacology, refer to the current Investigator's Brochure.
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5.2.5 non-clinical and clinical pharmacokinetics

Following oral administration of ibrutinib at doses ranging from 1.25 to 12.5 mg/kg/day as well as fixed dose levels of 420, 560, and 840 mg/day, exposure to ibrutinib increased as doses increased, with substantial inter-subject variability. The mean half-life (t1/2) of ibrutinib across 3 clinical studies ranged from 4 to 9 hours, with a median time to maximum plasma concentration (Tmax) of 2 hours. Administration of 420 mg ibrutinib with a high-fat breakfast in subjects with CLL approximately doubled the mean systemic exposure compared to intake after overnight fasting with median time to Tmax delayed from 2 to 4 hours. Ibrutinib was extensively metabolized to the dihydrodiol metabolite PCI-45227, a reversible inhibitor of BTK, with approximately 15 times lower inhibitory potency compared to ibrutinib. The metabolite-to-parent AUC ratio ranged from 0.7 to 3.4. Steady-state exposure of ibrutinib and PCI-45227 was less than 2-fold of first dose exposure.  
Data from clinical Study PCYC-04753 demonstrate that although ibrutinib is rapidly eliminated from the plasma after oral administration, once daily dosing with ibrutinib is adequate to sustain maximal pharmacodynamic activity for 24 hours post dose at dose levels ≥ 2.5 mg/kg. In Study PCYC-04753, the BTK occupancies for the 2.5 mg/kg/day to 12.5 mg/kg/day cohorts and for the 560 mg continuous dosing cohort were all above 90% at either 4 or 24 hours after drug administration.
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5.2.6 summaries of non-clinical pharmacology

For the most comprehensive nonclinical information regarding ibrutinib, refer to the current version of the Investigator's Brochure.
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5.2.6.1 non-clinical toxicology studies

In safety pharmacology assessments, no treatment-related effects were observed in the central nervous system or respiratory system in rats at any dose tested. Further, no treatment-related corrected QT interval (QTc) prolongation effect was observed at any tested dose in a cardiovascular study using telemetry-monitored dogs. Based on data from rat and dog including general toxicity studies up to 13 weeks duration, the greatest potential for human toxicity with ibrutinib is predicted to be in lymphoid tissues
(lymphoid depletion) and the gastrointestinal tract (soft feces/diarrhea with or without inflammation). Additional toxicity findings seen in only one species with no observed human correlate in clinical studies to date include pancreatic acinar cell atrophy (rat), minimally decreased trabecular and cortical bone (rat) and corneal dystrophy (dog). In vitro and in vivo genetic toxicity studies showed that ibrutinib is not genotoxic. In a rat embryo-fetal toxicity study ibrutinib administration was associated with fetal loss and malformations (teratogenicity) at ibrutinib doses that result in approximately 6 times and 14 times the exposure (AUC) in patients administered the dose of 560 mg daily, respectively.
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5.2.6.2 carcinogenesis mutagenesis impairment of

Carcinogenicity studies have not been conducted with ibrutinib.  
Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg. Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs.
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5.2.7 summaries of clinical studies

The initial study of ibrutinib in relapsed/refractory CLL patients demonstrated an ORR of 90%
but only a 7% CR rate with a median treatment duration of 23 months.36 For the most comprehensive clinical information regarding ibrutinib, refer to the current version of the Investigator's Brochure.
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5.2.8 major route of elimination

The results of human mass balance study of [14C]-ibrutinib conducted in 6 healthy male subjects demonstrated that less than 10% of the total dose of [14C]-ibrutinib is renally-excreted, whereas approximately 80% is recovered in feces. Subjects with mild and moderate renal insufficiency
(creatinine clearance > 30 mL/min) were eligible to enroll in Study PCYC-1102-CA in which pharmacokinetic (PK) assessments were included. No dose adjustment is needed for mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). There is no data in patients with severe renal impairment or patients on dialysis. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC
of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of ibrutinib in patients with hepatic impairment is currently in progress.
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5.2.9 safety profile

Pooled safety data for a total of 1,971 subjects treated with various therapies in combination with ibrutinib from 17 studies that have completed primary or final analysis included in the CSR as of 12 November 2019 are summarized below. Therapies used in combination with ibrutinib in these studies, included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and rituximab), cytarabine, azacytidine, dexamethasone, durvalumab, ofatumumab, lenalidomide with EPOCH-R (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone +/- rituximab), nivolumab, Obinutuzumab, rituximab, carfilzomib +/-
dexamethasone, pomalidomide and dexamethasone and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).  
| therapy (N = 1,971)                                                                                                                                                                                                                      |                                                                  |                          |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|--------------------------|
| Most frequently reported                                                                                                                                                                                                                 | Most frequently reported                                         | Most frequently reported |
| TEAEs > 20%                                                                                                                                                                                                                              | Grade 3 or 4 TEAEs > 3%                                          | Serious TEAEs > 2%       |
| Neutropenia Diarrhea Nausea                                                                                                                                                                                                              |                                                                  |                          |
| Thrombocytopenia Fatigue Anemia Pyrexia Cough                                                                                                                                                                                            |                                                                  |                          |
| Upper respiratory tract  infection Constipation                                                                                                                                                                                          | Neutropenia                                                      |                          |
| Thrombocytopenia Febrile neutropenia Pneumonia Hypertension                                                                                                                                                                              |                                                                  |                          |
| Neutrophil count decreased Anemia Fatigue Diarrhea Platelet count decreased Hypokalemia Lymphocyte count decreased White blood cell count  decreased Atrial fibrillation Hyponatremia Leukocytosis Leukopenia Lymphocyte count increased | Febrile neutropenia Pneumonia Atrial fibrillation Pyrexia Anemia |                          |
| For more detailed information, refer to the current version of the IB.                                                                                                                                                                   |                                                                  |                          |
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5.2.9.1 bleeding-related events

There have been reports of hemorrhagic events in subjects treated with ibrutinib both with and without thrombocytopenia. These include minor hemorrhagic events such as contusion, epistaxis, and petechiae; and some major hemorrhagic events, some fatal, including gastrointestinal bleeding, intracranial hemorrhage and hematuria. Use of ibrutinib in subjects requiring other anticoagulants or medications that inhibit platelet function increases the risk of major bleeding. A higher risk for major bleeding was observed with anticoagulant than with antiplatelet agents. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with ibrutinib. Monitor for signs and symptoms of bleeding. Subjects with congenital bleeding diathesis have not been studied. See Section 4.3.3.4 for guidance on concomitant use of anticoagulants, antiplatelet therapy and/or supplements. See Section 4.3.5 for guidance on ibrutinib management with surgeries or procedures. In an in *vitro* platelet function study, inhibitory effects of ibrutinib on collagen induced platelet aggregation were observed, refer to Section 4.3.3.4. Supplements such as fish oil and vitamin E preparations should be avoided.  
Ibrutinib should be held at least 3 to 7 days pre- and post-surgery, depending upon the type of surgery and the risk of bleeding.
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5.2.9.2 cardiac arrhythmias

Atrial fibrillation, atrial flutter and cases of ventricular tachyarrhythmia including some fatal events, have been reported in subjects treated with ibrutinib, particularly in subjects with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation.  
Periodically monitor subjects clinically for cardiac arrhythmia. Subjects who develop arrhythmic symptoms (eg, palpitations, lightheadedness, syncope, chest discomfort or new onset of dyspnea) should be evaluated clinically, and if indicated, have an ECG performed. For cardiac arrhythmias that persists, consider the risks and benefits of ibrutinib treatment and follow the protocol dose modification guidelines.
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5.2.9.3 cytopenias

Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were reported in subjects treated with ibrutinib. Monitor complete blood counts monthly.
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5.2.9.4 diarrhea

Diarrhea is the most frequently reported non-hematologic AE with ibrutinib monotherapy and combination therapy. Other frequently reported gastrointestinal events include nausea, vomiting, and constipation. These events are rarely severe and are generally managed with supportive therapies including antidiarrheals and antiemetics. Subjects should be monitored carefully for gastrointestinal AEs and cautioned to maintain fluid intake to avoid dehydration.  
Medical evaluation should be made to rule out other etiologies such as *Clostridium difficile* or other infectious agents. Should symptoms be severe or prolonged, follow the protocol dose modification guidelines.
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5.2.9.5 infections

Infections (sepsis, bacterial, viral, or fungal infections) were observed in subjects treated with ibrutinib therapy. Some of these infections have been associated with hospitalization and death. Consider prophylaxis according to standard of care in subjects who are at risk for opportunistic infections. Although causality has not been established, cases of progressive multifocal leukoencephalopathy (PML) and hepatitis B reactivation have occurred in subjects treated with ibrutinib. Subjects should be monitored for signs and symptoms (fever, chills, weakness, confusion, vomiting and jaundice) and appropriate therapy should be instituted as indicated.
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5.2.9.6 non-melanoma skin cancer

Non-melanoma skin cancers have occurred in subjects treated with ibrutinib. Monitor subjects for the appearance of non-melanoma skin cancer.
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5.2.9.7 rash

Rash has been commonly reported in subjects treated with either single agent ibrutinib or in combination with chemotherapy. Rash occurred at a higher rate in the ibrutinib arm than in the ofatumumab arm in Study 1112. Most rashes were mild to moderate in severity. Isolated cases of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS) have been reported in subjects treated with ibrutinib. Subjects should be closely monitored for signs and symptoms suggestive of SCAR including SJS. Subjects receiving ibrutinib should be observed closely for rashes and treated symptomatically, including interruption of the suspected agent as appropriate. In addition, hypersensitivity-related events including erythema; urticaria; and angioedema have been reported.
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5.2.9.8 lymphocytosis and leukostasis 5.2.9.1.1

Upon initiation of treatment, a reversible increase in lymphocyte counts (ie, ≥ 50% increase from baseline and an absolute count > 5000/µL), often associated with reduction of lymphadenopathy, has been observed in most subjects (66%) with CLL/ small lymphocytic lymphoma (SLL) treated with ibrutinib. This effect has also been observed in some subjects with MCL treated with ibrutinib. This observed lymphocytosis (increase in the number of circulating lymphocytes eg, > 400,000/µL) is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings. In both disease types, lymphocytosis typically occurs during the first few weeks of ibrutinib therapy (median time 1.1 weeks) and typically resolves within a median of 8.0 weeks in subjects with MCL and 14 weeks in subjects with CLL/SLL (range 0.1 to 104 weeks). When ibrutinib was administered in combination with BR or with obinutuzumab in subjects with CLL/SLL, lymphocytosis was infrequent (7% with ibrutinib + BR versus 6% with placebo + BR and 7% with ibrutinib + obinutuzumab versus 1% with chlorambucil + obinutuzumab). Lymphocytosis was not observed with WM treated with ibrutinib.
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5.2.9.1.2 leukostasis

There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number of circulating lymphocytes (> 400,000/µL) may confer increased risk. Consider temporarily withholding ibrutinib. Subjects should be closely monitored. Administer supportive care including hydration and/or cytoreduction as indicated. For subject and ibrutinib management guidance, refer to Section 6.2.1.2.
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5.2.9.9 tumor lysis syndrome

Tumor lysis syndrome has been reported with ibrutinib therapy. Subjects at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor subjects closely and take appropriate precautions.
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5.2.9.10 interstitial lung disease

Cases of interstitial lung disease (ILD) have been reported in subjects treated with ibrutinib. Monitor subjects for pulmonary symptoms indicative of ILD. If symptoms develop, interrupt ibrutinib and manage ILD appropriately. If symptoms persist, consider the risks and benefits of ibrutinib treatment and follow the protocol dose modification guidelines (see Section 6).
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5.2.9.11 hypertension

Hypertension has occurred in subjects treated with ibrutinib. Regularly monitor blood pressure in subjects treated with ibrutinib and initiate or adjust antihypertensive medication throughout treatment with ibrutinib as appropriate.  
Cerebrovascular Accidents Although causality has not been established, cases of cerebrovascular accident, transient ischemic attack, and ischemic stroke including fatalities have been reported with the use of ibrutinib in the post-marketing setting, with and without concomitant atrial fibrillation and/or hypertension. Regular monitoring and appropriate treatment of conditions that can contribute to the occurrence of these events is recommended.
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long-term safety

The long-term safety data over 5 years from 1,178 subjects (treatment-naїve CLL/SLL n = 162, relapsed/refractory CLL/SLL n=646, and relapsed/refractory MCL n=370) treated with ibrutinib were analyzed. The median duration of treatment for CLL/SLL was 51 months (range, 0.2 to 98 months) with 70% and 52% of subjects receiving treatment for more than 2 years and 4 years, respectively. The median duration of treatment for MCL was 11 months (range, 0 to 87 months) with 31% and 17% of subjects receiving treatment for more than 2 years and 4 years, respectively. The overall known safety profile of ibrutinib-exposed subjects remained consistent, other than an increasing prevalence of hypertension, with no new safety concerns identified. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 6% (year 1-2), 8% (year 2 - 3), 9% (year 3- 4), and 9% (year 4-5). The incidence for the 5-year period was 11%.
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5.2.9.12 rationale for the starting

This study uses the FDA approved dose of ibrutinib 420 mg PO daily for CLL/SLL. Dose reduction of ibrutinib is allowed for attributable toxicity as specified in Section 6.2.
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5.2.9.13 maximum allowable dose /

There are limited data on the effects of ibrutinib overdose. No maximum tolerated dose (MTD)
was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg/day
(1400 mg/day). In a separate study, 1 healthy subject who received a dose of 1680 mg experienced reversible Grade 4 hepatic enzyme increases (AST and ALT). There is no specific antidote to ibrutinib. Subjects who ingest more than the recommended dosage should be closely monitored and given appropriate supportive treatment.  
Refer to Section 7 for further information regarding AE reporting.
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5.2.9.14 treatment duration

All study participants will receive ibrutinib daily starting at Week 1 Day 1 and be dosed continuously throughout the study until completion of 2 years combined therapy with venetoclax, disease progression, development of intolerable side effects, need to initiate prohibited therapies, or participant withdrawal. Upon completion of ibrutinib + venetoclax combination treatment at Week 117, participants will have completed the trial and may transition off-study to receive commercial ibrutinib at the discretion of the investigator.
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5.3 study drug supply 5.3.1

Venetoclax will be supplied by Abbvie. 5.3.1.1 **Venetoclax Ordering** The investigational pharmacist will request drug supply using the form in Appendix H. The form should be sent to supplies.team@abbvie.com.  
5.3.2 **Ibrutinib Drug Supply**
Ibrutinib will be supplied by Pharmacyclics. 5.3.2.1 **Ibrutinib Ordering** The investigational pharmacist will request drug supply using the form in Appendix I. The form should be sent to ist.ctep@pcyc.com.
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5.4 venetoclax and ibrutinib accountability

All clinical supplies must be maintained under adequate security and stored under conditions specified on the label. The venetoclax tablets must be stored at 15° to 25°C (59° to 77°F).  
Ibrutinib must be kept in a locked limited access room. The study drug must not be used outside the context of the protocol. Under no circumstances should the Investigator or other site personnel supply ibrutinib or venetoclax to other Investigators, subjects, or clinics or allow supplies to be used other than as directed by this protocol. An Investigational Drug Accountability Log must be used for drug accountability. For accurate accountability, the following information must be noted when drug supplies are used during the study:
1. Study identification number 2. Subject identification number 3. Lot number(s) of ibrutinib or venetoclax dispensed for that subject 4. Date and quantity of drug dispensed 5. Any unused drug returned by the subject
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6 dose modifications and discontinuation

If one or more electrolyte changes (from the pre-dose value) suggestive of tumor lysis syndrome (TLS) occurs within 24 hours of venetoclax initiation (20 mg dose) or dose escalation (50, 100, 200, 400 mg doses) and is confirmed by a repeat laboratory test within 1 to 2 hours, no additional venetoclax doses will be administered until resolution (within normal range) of those laboratory abnormalities. Upon resolution of laboratory abnormalities, the subject will remain at the current dose level of venetoclax (eg, if receiving 20 mg, will remain at 20 mg) through 7 doses. The additional Warnings in the Package Insert are administration of live attenuated vaccines prior to, during, or after venetoclax treatment (prohibited in this protocol) and embryo-fetal toxicity.  
See also Section 6.3 Dose Modification for Both Venetoclax and Ibrutinib.
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6.2 ibrutinib dose modification

The dose of ibrutinib should be modified according to the dose modification guidelines in Table 4 if any of the following toxicities attributable to ibrutinib occur:
- Grade 3 or greater non-hematological toxicities.  
- Grade 3 or greater neutropenia with infection or fever - Grade 3 thrombocytopenia (< 50,000/µL) in the presence of clinically-significant bleeding events.  
- Grade 4 hematological toxicities, including thrombocytopenia < 20,000/µL.
If clinically indicated, the use of anticoagulants or antiplatelet agents may be considered for the thromboprophylaxis of atrial fibrillation (Section 4.3.3.4). Recommended dose modifications are described in Table 4 below.  
| Occurrence   | Action to be Taken                                                                                          |
|--------------|-------------------------------------------------------------------------------------------------------------|
| First        | Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; may restart at original dose level (420 mg/day) |
| Second       | Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at  ≤ 280 mg/day                        |
| Third        | Withhold ibrutinib until recovery to Grade ≤ 1 or baseline; restart at  ≤ 140 mg/day                        |
| Fourth       | Discontinue ibrutinib                                                                                       |  
A high number of circulating malignant cells (> 400,000/uL) may confer increased risk of leukostasis; these subjects should be closely monitored. Administer supportive care such as hydration and/or leukapheresis as indicated. Ibrutinib may be temporarily held.
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6.2.1.1 dose modification for hepatic-impaired

Subjects who develop acute hepatic toxicity with liver enzymes Grade 3 or higher while on study should be managed per standard dose modification guidelines in Section **Error! Reference** source not found.. Ibrutinib is metabolized in the liver. In the population PK analysis (1,202 subjects), 179 subjects (14.9%) had mild hepatic impairment according to National Cancer Institute criteria and 12 subjects (1.0%) had moderate hepatic impairment. These subjects did not show a significantly higher ibrutinib exposure compared with subjects with normal hepatic function. In a hepatic impairment study, data showed an increase in ibrutinib exposure. For subjects with mild liver impairment (Child-Pugh class A), the recommended dose is 280mg
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table 4. ibrutinib dose modifications

E
daily. For subjects with moderate liver impairment (Child-Pugh class B), the recommended dose is 140mg daily. Monitor subjects for signs of ibrutinib toxicity and follow dose modification guidance as needed. It is not recommended to administer ibrutinib to subjects with severe hepatic impairment Subjects with clinically significant chronic hepatic impairment at the time of Screening (Child- Pugh class C) are excluded from study participation. Concomitant use of strong CYP inhibitors is not permitted in subjects with chronic hepatic impairment. Refer to Appendix D for Child-Pugh classification. Please refer to table below for dose modifications due to hepatic impairment.  
| Child Pugh class  C (Severe hepatic  impairment)                                                |                                                     |                 |          |                 |                         |
|-------------------------------------------------------------------------------------------------|-----------------------------------------------------|-----------------|----------|-----------------|-------------------------|
| Child Pugh class A (Mild hepatic  impairment)*                                                  | Child Pugh Class B (Moderate hepatic  impairment)** |                 |          |                 |                         |
| Ongoing at  time of  enrollment                                                                 | Develops  during  study                             | Ongoing at time | Develops | Develops during |                         |
| of enrollment                                                                                   | during study                                        | study           |          |                 |                         |
| Ibrutinib  Dose  (daily)                                                                        | 280 mg                                              | 280mg           | 140 mg   | 140 mg          | Hold until  improves to |
| moderate [Class  B] or better)                                                                  |                                                     |                 |          |                 |                         |
| * If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In |                                                     |                 |          |                 |                         |  
Table . Dose Modification Guidance for Hepatic Impaired Subjects
* If further reduction is needed due to non-hepatic toxicity, dose may be reduced to 140 mg. In the event that additional reduction is needed, ibrutinib should be held for non-hepatic toxicity until resolution.  
** If further reduction is needed due to non-hepatic toxicity, ibrutinib should be held until resolution.
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6.2.1.2 leukocytosis / leukostasis

There were isolated cases of leukostasis reported in subjects treated with ibrutinib. A high number of circulating white blood cells (>400,000/µL) may confer increased risk of leukostasis; these subjects should be closely monitored. Administer supportive care such as hydration and/or leukapheresis as indicated. Consider temporarily withholding ibrutinib, and medical monitor should be contacted.
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6.3 dose modification for both

If the events below occur, no additional venetoclax doses will be administered until resolution of those laboratory abnormalities (≤ Grade 1), and ibrutinib dosing should continue or be discontinued per Table 4.  
- Grade 4 ANC (< 500/µL) for more than 7 days. See Section 4.3.2 for instructions regarding the use of growth factor support.  
- Any other Grade 4 toxicity, or unmanageable Grade 3 toxicity.
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6.4 treatment discontinuation

Study treatment with venetoclax and ibrutinib will be permanently discontinued for any subject if any of the following occur.  
- Grade 4 treatment-related (ie, possibly-, probably-, or definitely-related) non-hematologic toxicity.  
- Grade 4 neutropenia lasting > 21 days - Grade 4 thrombocytopenia lasting > 21 days or associated with clinically-significant bleeding (requiring > 3 units of packed red blood cells within 24 hours to replace loss OR bleeding from a site which in the Investigator's opinion is a potential life-threatening source irrespective of blood loss)
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7 adverse events and reporting

Timely, accurate, and complete reporting and analysis of safety information from clinical studies are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by regulatory agencies worldwide.  
Investigators will assess the occurrence of adverse events and serious adverse events at all subject evaluation time points during the study. All adverse events (AE) and serious adverse events (SAE) whether volunteered by the subject, discovered by study personnel during questioning, detected through physical examination, clinically significant laboratory test, or other means, will be recorded. Each recorded adverse event or serious adverse event will be described by its duration (ie, start and end dates), severity, regulatory seriousness criteria (if applicable), suspected relationship to the investigational product, and any actions taken. The Protocol Director or designee will assess each AE to determine whether it is unexpected according to the Investigator's Brochure; Protocol; and Informed Consent, and whether it is related to the investigation (eg, study procedures) and/or the investigational agent. All SAEs will be tracked until resolution, or until at least 30 days after the last dose of the study treatment.
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7.1 adverse events definition

An AE is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an investigational study drug, whether or not considered related to the study drug (ICH-E2A, 1995). For the purposes of this clinical study, AEs include events which are either new or represent detectable exacerbations of pre-existing conditions.  
The term "disease progression" should not be reported as an adverse event term. As an example, "worsening of underlying disease" or the clinical diagnosis that is associated with disease progression should be reported.  
Adverse events may include, but are not limited to:  
- Subjective or objective symptoms provided by the subject and/or observed by the Investigator or study staff including laboratory abnormalities of clinical significance.  
- Any AEs experienced by the subject through the completion of final study procedures. - AEs not previously observed in the subject that emerge during the protocol-specified AE
reporting period, including signs or symptoms associated with the underlying disease that were not present before the AE reporting period
- Complications that occur due to protocol-mandated interventions (eg, invasive procedures such as biopsies).
The following are NOT considered AEs:
- **Pre-existing condition:** A pre-existing condition (documented on the medical history CRF) is not considered an AE unless the severity, frequency, or character of the event worsens during the study period.  
- **Diagnostic Testing and Procedures:** Testing and procedures should not to be reported as AEs or SAEs, but rather the cause for the test or procedure should be reported.  
- **Asymptomatic Treatment-related Lymphocytosis:** This event should also not be considered an AE. Subjects with treatment-related lymphocytosis should remain on study treatment and continue with all study-related procedures.
An "unexpected" AE is an AE that is not listed in the Investigator's Brochure/package insert or is not listed at the specificity or severity that has been observed. "Unexpected" also refers to AEs that are mentioned in the Investigator's Brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as occurring with the study drug under investigation.
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7.1.1 serious adverse events definition

For this investigational drug study, AEs will be determined to be Serious Adverse Events (SAEs)
per 21CFR§312.32(a) and ICH GCP E6r1 (revision 1). An adverse event is considered
"serious" if, in the opinion of the Protocol Director; investigator; or sponsor, it results in any of the following.  
- Death
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- life-threatening ie immediate risk

- Requires, results in, or prolongs inpatient hospitalization - Is a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
- Is a congenital anomaly/birth defect in the offspring of a study participant - Jeopardizes the subject, in the opinion of the Protocol Director; investigator; or sponsor
- Requires medical or surgical intervention to prevent one of the outcomes listed in this definition, in the opinion of the Protocol Director; investigator; or sponsor The following are NOT considered SAEs:
- **Pre-planned or elective hospitalization:** A hospitalization planned before signing the informed consent form is not considered an SAE, but rather a therapeutic intervention.  
However, if during the pre-planned hospitalization an event occurs, which prolongs the hospitalization or meets any other SAE criteria, the event will be considered an SAE. Surgeries or interventions that were under consideration, but not performed before enrollment in the study, will not be considered serious if they are performed after enrollment in the study for a condition that has not changed from its baseline level. Elective hospitalizations for social reasons, solely for the administration of chemotherapy, or due to long travel distances are also not SAEs.
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7.2 adverse event reporting

Adverse events (AEs) will be graded according to CTCAE v4.03, except as noted below. The CTCAE v4.03 displays Grades 1 through 5 with unique clinical descriptions of severity for each referenced AE. Should a subject experience any AE not listed in the CTCAE v4.03 the following grading system should be used to assess severity:  
- Grade 1 (Mild AE) - experiences which are usually transient, requiring no special treatment, and not interfering with the subject's daily activities
- Grade 2 (Moderate AE) - experiences which introduce some level of inconvenience or concern to the subject, and which may interfere with daily activities, but are usually ameliorated by simple therapeutic measures
- Grade 3 (Severe AE) - experiences which are unacceptable or intolerable, significantly interrupt the subject's usual daily activity, and require systemic drug therapy or other treatment
- Grade 4 (Life-threatening or disabling AE) - experiences which cause the subject to be in imminent danger of death
- Grade 5 (Death related to AE) - experiences which result in subject death
All treatment-emergent AEs will be captured from the first dose of study drug. SAEs will be reported to the Sponsor from the time of ICF signing. Both serious and non-serious AEs will be recorded in the eCRF from the first dose of study drug until 30 days after the last dose of study drug. Serious adverse events reported after 30 days following the last dose of study drug should also be reported if considered related to study drug. Resolution information after 30 days should be provided. Progressive disease should NOT be reported as an event term, but instead symptoms/clinical signs of disease progression may be reported.  
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug, must be recorded using medical terminology in the source document. All records will need to capture the details of the duration and the severity of each episode, the action taken with respect to the study drug, investigator's evaluation of its relationship to the study drug, and the event outcome. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory infection"). Investigators must record in the eCRF their opinion concerning the relationship of the adverse event to study therapy All deaths should be reported with the primary cause of death as the AE term, as death is typically the outcome of the event, not the event itself. If a death occurs within 30 days after the last dose of study drug, the death must be reported as a serious adverse event. All serious adverse events (SAEs) and AESIs (initial and follow-up information) will be reported to the FDA Medwatch (Form 3500A) or Suspect Adverse Event Report (CIOMS Form 1) IRB
Reporting Form and sent via email (AEintakeCT@pcyc) or fax (408-215-3500) to Pharmacyclics Drug Safety, or designee, within 15 days of the event. Pharmacyclics may request follow-up and other additional information from the Sponsor Investigator. All serious adverse events (SAEs) CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the Stanford Cancer Institute (SCI) Data and Safety Monitoring Committee (DSMC) using the study-specific CRF regardless of the event's relatedness to the investigation. Following review by the DSMC, events meeting the IRB definition of
"Unanticipated Problem" will be reported to the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for deaths or life-threatening experiences AEs, serious or otherwise, will be attributed to study treatment as follows:
- **Definite**: The AE is clearly related to the study treatment.  
- **Unrelated**: The AE is clearly NOT related to the study treatment.  
All serious adverse events (SAEs) will be followed until the SAE(s) is(are) resolved, stabilized, returned to baseline, attributed to agents other than the study drugs or to factors unrelated to study conduct, or until additional information cannot be obtained (subject or health care practitioner refusal to provide additional information, lost to follow-up after demonstration of due diligence with follow-up efforts), whichever is longer.  
| -   | Probable:   | The AE is likely related to the study treatment.     |
|-----|-------------|------------------------------------------------------|
| -   | Possible:   | The AE may be related to the study treatment.        |
| -   | Unlikely:   | The AE is doubtfully related to the study treatment. |  
Adverse events that are serious and unexpected suspected adverse reactions, ie, are possibly, probably, or definitely related to the study drugs venetoclax and ibrutinib, will be reported to the FDA via IND Safety Report [21CFR§312.32] within 14 calendar days, or within 7 calendar days if the event is an unexpected fatal or life-threatening suspected adverse reaction.
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7.3 safety monitoring

This study is monitored by the Stanford Data and Safety Monitoring Committee (DSMC). SAEs will be reported by the study team to Stanford DSMC per the current Stanford SOP. SAEs that meet the definition of an "Unanticipated Problem" per the Stanford DSMC will be reported to the Stanford IRB using eProtocol within 10 working days of the Stanford DSMC's report to the Protocol Director regarding the event (within 5 working days for deaths or life-threatening events). See also Section 10.3 Data and Safety Monitoring Plan.  
All serious adverse events (SAEs) that are CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study specific CRF regardless of the event's relatedness to the investigation. All SAEs will be reported will be reporting to the IRB in the annual Continuing Review, or the Final Report, that is submitted to the IRB.
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7.4 adverse events of special

A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis from the initial malignancy). All new malignant tumors including solid tumors, skin malignancies and hematologic malignancies will be reported as SAEs per the current Stanford SOP, for the duration of study treatment and during any protocol-specified follow-up periods including post-progression follow-up for overall survival.
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7.4.1.2 secondary malignancy

In the context of a clinical study, a secondary malignancy is a cancer caused by the investigational agent/intervention, radiation, or chemotherapy. A secondary malignancy is not considered a metastasis of the initial neoplasm. All secondary malignancies will be reported as SAEs per the current Stanford SOP. Three options/examples are available to describe the event:
- Leukemia secondary to oncology chemotherapy [eg, acute myeloid leukemia (AML)]  
- Myelodysplastic syndrome (MDS) - Treatment-related secondary malignancy
By definition, secondary malignancies are serious and related adverse events, and require expedited reporting.
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7.4.2 other adverse events of

Specific adverse events, or groups of adverse events, will be followed as part of standard safety monitoring activities. In addition to normal reporting, these events (regardless of seriousness)
will be reported on the Serious Adverse Event Report Form and sent via email or fax to Pharmacyclics Drug Safety, Pharmacovigilance & Epidemiology (DSP&E), or designee within 15 days of awareness.  
- Major Hemorrhage, as defined by any of the following:  
o Any treatment-emergent hemorrhagic adverse events of Grade 3 or higher. * o Any treatment-emergent serious adverse events of bleeding of any grade. o Any treatment-emergent central nervous system hemorrhage/hematoma of any grade.
* All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or higher AE per CTCAE v4.03.
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7.4.2.2 eye-related adverse events

New or worsening eye-related symptoms that are Grade 2 or higher, or a symptom that was Grade 2 or higher at baseline worsens, should be evaluated by an ophthalmologist whose findings should be reported in the CRF.
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7.4.2.3 pregnancy

Before study enrollment, subjects must agree to take appropriate measures to avoid pregnancy.  
However, should a pregnancy occur in a female study subject, consent to provide follow-up information regarding the outcome of the pregnancy and the health of the infant until 30 days old will be requested. A female subject must immediately inform the Investigator if she becomes pregnant from the time of consent to 90 days after the last dose of study drug. A male subject must immediately inform the Investigator if his partner becomes pregnant from the time of consent to 3 months after the last dose of study drug. Any female subjects receiving study drug(s) who become E
pregnant must immediately discontinue study drug. The Investigator should counsel the subject, discussing any risks of continuing the pregnancy and any possible effects on the fetus.  
Men should be advised not to father a child or donate sperm while receiving ibrutinib, and for 3 months following completion of treatment.  
Although pregnancy itself is not regarded as an adverse event, the outcome will need to be documented. Any pregnancy occurring in a subject or subject's partner from the time of consent to 30 days after the last dose of study drug must be reported. Any occurrence of pregnancy must be reported to Pharmacyclics Drug Safety, or designee, per SAE reporting timelines. All pregnancies will be followed for outcome, which is defined as elective termination of the pregnancy, miscarriage, or delivery of the fetus. Pregnancies with an outcome of live birth, the newborn infant will be followed until 30 days old by completing will need to be reported to Pharmacyclics per SAE reporting timelines. Any congenital anomaly/birth defect noted in the infant must be reported as a serious adverse event.
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7.5 case report forms (crfs)

Both SAEs and non-serious AEs will be clearly described in source documentation and listed on study-specific Case Report Forms (CRFs or eCRFs).
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8.1 pharmacokinetics assessments collected at

Pharmacokinetic samples for ibrutinib will be collected pre-dose (window: 30 to 60 minutes before dose), then 1 hour (window: 45 to 75 minutes); 2 hours (window: 1.5 to 2.5 hours); 4 hours (window: 3.5 to 4.5 hours); and 6 hours (window 5.5 to 6.5 hours) post-ibrutinib administration on the first day of ibrutinib dosing (Week 1 Day 1) and each day when dosed in combination with newly-escalated dose of venetoclax in all subjects enrolled in the study.  
Venetoclax:
Pharmacokinetic samples for venetoclax will be collected at 0, 8, 24 hours with each dose-escalation of venetoclax.
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8.2 biomarker assessments blood for

Approximately 4 mL of blood will be collected by venipuncture into a heparin vacutainer from subjects at the following time point:
- Screening or Week 1 Day 1 pre-dose
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blood for mutation profiling

Approximately 10 mL of blood will be collected by venipuncture into ACD vacutainers from all subjects at the following time points:
- Week 1 Day 1 pre-dose - Final Visit/Time of Relapse Blood/Bone Marrow for ClonoSEQ **Sequencing**
Approximately 10 mL of blood will be collected by venipuncture into EDTA tube from all subjects at the following time points: Blood:
- Week 1 Day 1 pre-dose or anytime between screening and start of treatment - Within 1 month of completion of therapy at Week 117 Bone Marrow:
- Week 62
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9 treatment assessments and study

Subjects will undergo screening procedures as described within Section 3 and Section 9.2.1 within 28 days prior to first study drug administration. Signed informed consent will be obtained from the subject or the subject's legally acceptable representative before any study-specific procedures are undertaken or before any prohibited medications are withheld from the subject to participate in this study. After signing the informed consent form, screening and meeting inclusion/exclusion criteria for trial enrollment, Stanford will assign subjects a unique consecutive subject number.
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9.1.2 treatment phase

Following completion of the Screening Visit and once eligibility has been confirmed, subjects are enrolled. Enrollment should occur as close to the time of the expected first dose as possible.  
During the treatment and follow-up periods, AE and assessment will occur on an ongoing basis. Local labs will be used to guide all dosing-related decisions.  
Treatment will initiate on Week 1 Day 1 with ibrutinib 420 mg PO daily. For tumor lysis prophylaxis, all subjects will be classified into 3 risk categories based on the risk for developing TLS prior to venetoclax administration (ie, after 8 weeks of ibrutinib administration) as detailed in Section 4.3.1.  
Subjects in low category and medium risk category with CrCl ≥ 80 mL/min and low tumor burden will begin treatment with venetoclax in the outpatient setting with an initial dose of 20 mg venetoclax on Week 9 Day 1. If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same dose will be continued until Day 7 in the outpatient setting. Subjects with no laboratory abnormalities suggestive of LTLS will escalate to a dose of 50 mg venetoclax on Week 10 Day 1 in the outpatient setting.  
Medium risk subjects with CrCl < 80 mL/min and higher tumor burden may be admitted to the hospital at the investigator discretion to begin venetoclax with an initial dose of 20 mg on Week 9 Day 1. If no significant findings suggestive of clinical or lab TLS occur within 24 hours, the same dose will be continued until Day 7 in the outpatient setting. Subjects may be hospitalized prior to the first dose increment if they continue to have Cr Cl < 80 mL/min and higher tumor burden at the investigator's discretion. Subjects with no laboratory abnormalities suggestive of LTLS will escalate to a dose of 50 mg venetoclax on Week 10 Day 1 in the outpatient setting. All high-risk subjects will be admitted to the hospital and begin treatment with venetoclax with an initial dose of 20 mg on Week 9 Day 1. If no significant findings suggestive of clinical or lab TLS
occur within 24 hours, the same dose will be continued until Day 7 in the outpatient setting. Each subject's risk status will be reassessed prior to subsequent dose increments to determine the need for hospitalization.  
If no significant findings occur within 24 hours at dose escalation, the study drug will be continued at the same dose from Days 2 through 7. If there is indication of lab or clinical TLS the study drug dose will be held till resolution of all findings. TLS management will be implemented as appropriate.  
A lower starting dose to the lead-in regimen may be implemented for individual subject(s) at particularly high-risk for TLS.
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9.2 study procedures and assessments

All study procedures are discussed in detail in this section except for adverse event information
(discussed in Section 7). Procedures performed at Screening will serve as baseline unless repeated prior to dosing in which case the latest prior to dosing will serve as baseline.
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9.2.1 study assessments medical and

Screening Visit assessment will include:
- Complete medical history, including documentation of any clinically significant medical condition  
- History of tobacco and alcohol use - Detailed oncology history including:
o Histology o Cytogenetics o Date of CLL diagnosis o Stage at diagnosis o Any surgical procedures o Treatments administered (including dates, type of modality, response to treatment and reason for treatment discontinuation)
- Detailed prior and concomitant medication usage including dates of usage and dosing information for all medications and supplements taken
Week 1 Day 1: Any changes observed from the Screening assessments (prior to dosing) will be recorded in the subject's medical history.
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adverse event and concomitant medication

Medication (prescription or over-the-counter, including vitamins and herbal supplements) will be recorded beginning with the Screening Visit through the end of the study. At each visit, including the Final Visit and the 30-Day Safety Follow-Up Visit, the subject's medical history will be reviewed and any changes from baseline will be recorded.
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vital signs physical examination ecog

Body temperature (oral or tympanic), weight, blood pressure and heart rate, evaluation of ECOG performance status (see Appendix B) as well as a complete physical examination including evaluation of the head, eyes, ears, nose, throat, cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal and neurologic systems will be performed at screening, Week 1 Day 1, Week 5 Day 1, Weekly from Week 9 Day 1 through Week 14 Day 1, every 4 weeks from Week 18 Day 1 through Week 30 Day 1, and every 12 weeks starting on Week 38 day 1. ECOG status, vital signs and a complete physical exam should be performed at the Final Visit and 30-Day Safety Follow-Up Visit.
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subject calendars/diaries

Subject calendars/diaries will be provided. Subjects will be instructed to bring their calendars/diaries for review at:  
- Week 1 Day 1 - Week 5 Day 1 - Week 9-14 Day 1 - Week 18 Day 1 - Week 22 Day 1
- Week 26 Day 1 - Week 30 Day 1 - Week 38 Day 1 and every 12 weeks thereafter through Week 117
Subjects will be instructed to record the date and time each dose of study drug is taken,
(indicating if any doses of study drug are missed) and the timing of each dose relative to the subject's first meal of the day. Subjects will also be instructed to record adverse events and concomitant medications.  
The calendars/diaries are to be reviewed at each visit and relevant pages are to be photocopied by study staff. At the end of the subject's participation in the study, the calendars/diaries are to be returned to the site and appropriately filed with the subject's source documents for this study.
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9.2.2 efficacy evaluations

Response will be assessed by the investigator based on analysis of clinical laboratory tests, complete physical examination, and CT scan of involved anatomic regions (or MRI if CT is medically contraindicated) as well as bone marrow aspirate and biopsy with MRD assessment.  
Subjects will be evaluated with documentation of response (CR/PR/SD/progressive disease) per 2008 Modified IWCLL NCI-WG Criteria for Tumor Response (Appendix D).  
- Week 9 Day 1  
- Week 14 Day 1, and every 4 weeks through Week 30 Day 1 - starting Week 38 Day 1, every 12 weeks thereafter CT scans (or MRI) will be obtained
- Week 9 Day 1 - Week 38 Day 1 - Week 62 Day 1 - Within 1 month of completion of therapy
Bone marrow aspirate and biopsy will be obtained Week 62 and within 1 month of completion of therapy
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minimal residual disease (mrd) assessment

Subjects will have MRD assessed in a bone marrow aspirate sample using sensitive flow cytometry as well as ClonoSEQ.
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9.2.3 study diagnostics / procedures

For female subjects of childbearing potential, pregnancy testing must be performed as follows:  
- Screening - quantitative beta-human chorionic gonadotropin (β-hCG) serum pregnancy test.  
- Week 1 Day 1: Urine test, if it has been > 7 days since obtaining the Screening serum pregnancy test results.
Pregnancy test results must be reviewed and determined to be negative prior to dosing.  
Subjects considered not of childbearing potential must be documented as being surgically sterile or postmenopausal for at least ≥ 1 year.
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hematology and chemistry

Chemistry and hematology samples will be collected at the following time points (refer to Table 5 for specific tests):
- Screening  
- Week 1 Day 1
- Week 5 Day 1 - For Weeks 9-13 refer to Section 4.3.1 Prophylaxis and Management of Tumor Lysis Syndrome and Appendix E Recommendations for Initial Management of Electrolyte Abnormalities and Prevention of Tumor Lysis Syndrome (TLS) for monitoring during intra-patient dose escalation of venetoclax
- Week 14 Day 1
- Week 18 Day 1 - Week 22 Day 1
- Week 26 Day 1
- Week 30 Day 1 - Week 38 Day 1and every 12 weeks thereafter
- Final Visit - 30-Day Safety Follow-Up Visit
- As needed throughout study
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coagulation panel

PT/aPTT samples will be collected at the following time points:
- Screening
- Week 9 Day 1 Note: Coagulation panel may be collected within 72 hours prior to the scheduled visit.
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urinalysis

Urinalysis samples will be collected at:
- Screening Note: Urinalysis may be collected within 72 hours prior to the scheduled visit.
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viral serologies

A sample for viral serologies to identify Hepatitis B (HBsAg, anti-HBs, total anti-HBc, IgM
anti-HBc), Hepatitis C (HCV) antibody or RNA, cytomegalovirus, varicella zoster virus, herpes simplex virus, and Epstein-Barr virus will be collected at the following time points:
- Screening - As needed for suspicion of viral infection  
| Table 5. Clinical Laboratory Tests                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Hematology  Hematocrit Hemoglobin Red Blood Cell (RBC) count White Blood Cell (WBC) count Neutrophils Bands Lymphocytes Monocytes Basophils Eosinophils Platelet count (estimate not acceptable) Mean platelet volume (MPV) Mean corpuscular hemoglobin (MCH) Mean corpuscular volume (MCV) Mean corpuscular hemoglobin concentration  (MCHC) | Clinical Chemistry Blood Urea Nitrogen (BUN) Creatinine Total bilirubin Serum glutamic-pyruvic transaminase  (SGPT/ALT) Serum glutamic-oxaloacetic transaminase  (SGOT/AST) Alkaline phosphatase Sodium Potassium Calcium Inorganic phosphorus Uric acid Total protein Glucose Albumin Lactate dehydrogenase (LDH) Magnesium Chloride Bicarbonate G6PD assay (prior to rasburicase only) |  
E  
| Urinalysis Specific gravity Ketones pH Protein Blood Glucose                                                       | Coagulation Prothrombin time (PT) Activated partial thromboplastin time (aPTT)   |
|--------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|
| Note for samples from patients treated with rasburicase: rasburicase causes enzymatic degradation of the uric acid |                                                                                  |  
Note for samples from patients treated with rasburicase: rasburicase causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation. Uric acid must be analyzed in plasma. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. **Immediately** immerse plasma samples for uric acid measurement in an ice water bath. Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection.
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computed tomography (ct) or magnetic

A CT scan with contrast (unless medically contraindicated) must be performed within 28 days prior to study drug administration. A CT scan without contrast or a MRI may be substituted when clinically warranted. Subjects should have the same imaging test performed through the study for accurate comparison. A CT scan will also be performed at the completion of Week 8, 37 and 61 and should be performed within 1 week of the Week 38 and Week 62 scheduled visits and within 1 month of the completion of therapy. If a subject exhibits clinical signs of disease progression (increased lymphadenopathy, hepatosplenomegaly) without meeting laboratory criteria for progression, a CT scan will be performed within 2 weeks to confirm or rule out progressive disease as described in Appendix D according to the Modified IWCLL Criteria for Tumor Response.
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bone marrow aspirate and biopsy

A bone marrow aspirate and biopsy will be done at Screening (within 28 days prior to the first dose of study drug). The bone marrow aspirate and biopsy should be performed after all other eligibility criteria have been met, unless otherwise obtained through standard of care. Bone marrow aspirates and biopsies, immunohistochemical analysis and cytogenetics performed as standard of care throughout the study should also be documented.  
If the subject meets clinical/laboratory criteria and a confirmatory CT scan meets criteria for a CR, a bone marrow aspirate and biopsy should be repeated. The order of collections from the bone marrow aspirate and biopsy should be 1) MRD assessment and 2) clinical assessment.
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12-lead electrocardiogram

A 12-lead resting ECG will be obtained at the following:
- Screening  
- As clinically indicated
The ECG results will be used by the investigator for subject safety assessments, including adverse event determination and management and termination of subjects from the study.  
- ECG results will be summarized as follows:
- Normal ECG - Abnormal ECG - not clinically significant  
- Abnormal ECG - clinically significant
- Unable to evaluate
The QT interval measurement will be documented only if a "prolonged QT" is observed.  
Correction by the Fridericia formula (QTcF) is preferred. The original ECG tracing will be retained in the subject's records at the study site.
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9.3 table of assessments /

| Treatment Phase Week 38  Day 1- Wk 62 Day  Week 61  - Wk   | Final                         |       |          |            |    |    |    |    |    |
|------------------------------------------------------------|-------------------------------|-------|----------|------------|----|----|----|----|----|
| Day 1                                                      | visit                         |       |          |            |    |    |    |    |    |
| 2                                                          | Q12 weeks                     | 117   |          |            |    |    |    |    |    |
| Week 14,                                                   |                               |       |          |            |    |    |    |    |    |
| Weeks 9-13 18, 22, 26,  30 Day 1                           |                               |       |          |            |    |    |    |    |    |
| Screenin                                                   |                               |       |          |            |    |    |    |    |    |
| Study Visits                                               | g Phase Week  Week 5  1 D1 D1 |       |          |            |    |    |    |    |    |
| Study Visit Windows                                        | -28 days                      | exact | ± 7 days | + 30  days |    |    |    |    |    |
| Procedures                                                 |                               |       |          |            |    |    |    |    |    |
| Informed consent                                           | X                             |       |          |            |    |    |    |    |    |
| Medical history                                            | X                             |       |          |            |    |    |    |    |    |
| Confirm eligibility and enroll                             | X                             |       |          |            |    |    |    |    |    |
| Cumulative Illness Rating Scale  (CIRS)                    | X                             |       |          |            |    |    |    |    |    |
| Concomitant medications                                    | X                             | X     | X        | X          | X  | X  | X  | X  |    |
| Adverse events b                                           | X                             | X     | X        | X          | X  | X  | X  | X  |    |
| Study drug compliance review c                             | X                             | X     | X        | X          | X  |    |    |    |    |
| Height                                                     | X                             |       |          |            |    |    |    |    |    |
| Physical exam, vital signs, weight,  ECOG                  | X                             | X     | X        | X          | X  | X  | X  | X  |    |
| Disease assessment: CT/MRI scan                            | X j                           | X f   | X f      | X f        |    |    |    |    |    |
| Bone marrow biopsy/aspirate h                              | X                             | X     |          |            |    |    |    |    |    |
| Disease-related symptoms i                                 | X                             | X     | X        | X          | X  | X  | X  | X  |    |
| Overall response assessment                                | X                             | X     | X        | X          | X  |    |    |    |    |
| Hematology                                                 | X                             | X     | X        | X          | X  | X  | X  | X  |    |
| Serum chemistry                                            | X                             | X     | X        | X          | X  | X  | X  | X  | X  |
| Creatinine clearance  (Cockcroft-Gault)                    | X                             | X     |          |            |    |    |    |    |    |
| Cytogenetic, CLL FISH panel                                | X                             |       |          |            |    |    |    |    |    |
| Hepatitis serologies                                       | X                             |       |          |            |    |    |    |    |    |
| Coagulation panel                                          | X                             | X l   |          |            |    |    |    |    |    |
| 12-lead ECG k                                              | X                             |       |          |            |    |    |    |    |    |
| Any new anticancer therapy                                 | Page 73 of 111                |       |          |            |    |    |    |    |    |  
E  
| Treatment Phase Week 38  Day 1- Wk 62 Day  Week 61  - Wk   | Final                         |          |
|------------------------------------------------------------|-------------------------------|----------|
| Day 1                                                      | visit                         |          |
| 2                                                          | Q12 weeks                     | 117      |
| PK sample collection                                       | X d                           | X d      |
| Mutational profiling                                       | X a                           | Week 14, |
| Weeks 9-13 18, 22, 26,  30 Day 1                           |                               |          |
| Screenin                                                   |                               |          |
| Study Visits                                               | g Phase Week  Week 5  1 D1 D1 |          |
| MRD assessment m                                           | X                             | X        |  
| Screenin                                                                                                                                     |                           |                 |
|----------------------------------------------------------------------------------------------------------------------------------------------|---------------------------|-----------------|
| Study Visits                                                                                                                                 | g Phase                   | Treatment Phase |
| Study Drug Administration and Dispensation Venetoclax                                                                                        | Continuous daily dosing   |                 |
| Dispensed weekly during dose ramp-up and every specified  study visit thereafter through Week 117 Intra-patient dose  400 mg daily ramp-up   |                           |                 |
| Ibrutinib 420 mg PO                                                                                                                          | Continuous daily dosing g |                 |
| Dispensed every 4 weeks from Week 1 through Week 30 and every  specified study visit thereafter through Week 117                             |                           |                 |
| D = day; Term = treatment termination; d/c = discontinuation; PD = progressive disease; FU = follow-up; (x) = not all visits or all subjects |                           |                 |  
Ibrutinib 420 mg PO Continuous daily dosing g Dispensed every 4 weeks from Week 1 through Week 30 and every specified study visit thereafter through Week 117 D = day; Term = treatment termination; d/c = discontinuation; PD = progressive disease; FU = follow-up; (x) = not all visits or all subjects a To be collected pre-dose b AEs are reported from the time the patient signs the Informed Consent Form until 30 days following last dose of study drug. In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported as adverse events for the duration of the study treatment and during any protocol-specified follow-up periods including post-progression follow-up for overall survival.  
c Includes patient instruction and routine review of study drug diary and evaluation of contents of study drug containers from home administration d At SCI only: Ibrutinib: Pre-dose (window: 30 to 60 minutes before dose), then 1 hour (window: 45 to 75 minutes), 2 hours (window: 1.5 to 2.5 hours), 4 hours
(window: 3.5 to 4.5 hours), and 6 hours (window: 5.5 to 6.5 hours) post-dose on the first day of ibrutinib dose administration (Week 1 Day 1) and each day when dosed in combination with new dose of venetoclax. Venetoclax: 0 hour, then 8 hour and 24 hour post-dose with each Day 1 dose increase of venetoclax f Between Week 8 Day 1 and prior to Week 9 Day 1; Week 38 Day 1 +/- 7 days; Week 62 Day 1 +/- 7 days; within 1 month after completion of therapy; within 2 weeks of suspected disease progression g Day 1 dose of Cycle 1 and each PK day should be administered at the investigational site. Subsequent daily doses may be self-administered at home. h Bone marrow biopsy and/or aspirate should be performed at Screening within 28 days before the first dose of study drug, Week 62, and within 1 month of completion of therapy. Marrow collected to confirm CR should have minimal residual disease (MRD) assessed by flow cytometry and ClonoSEQ on the aspirate i Disease-related symptoms include weight loss, fatigue, fever, night sweats, abdominal pain/discomfort due to splenomegaly including early satiety, and anorexia.  
j Baseline CT scan can be performed within 28 days prior to study drug administration k ECG's may be performed at the investigator's discretion, particularly in subjects with arrhythmic symptoms (eg, palpitations, lightheadedness) or new onset dyspnea l Coagulation test to be done Week 9, Day1 only E
m Bone marrow aspirate for ClonoSEQ between Screening and start of therapy, at Week 62, and within 1 month of completion of therapy at Week 117. Bone marrow aspirate for MRD flow assessment at Week 62 and within 1 month of completion of therapy at Week 117.
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9.4 end-of-study

The study will end after the last subject completes therapy. This is expected to be up to 4 years total, depending on the accrual rate.
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9.4.1 study discontinuation

Per the IST Agreement, the Investigator reserves the right to terminate the study at any time. Should this be necessary, both the Investigator will arrange discontinuation procedures in partnership with Pharmacyclics. In terminating the study, the Investigator will assure that adequate consideration is given to the protection of the subjects' interests. Pharmacyclics may terminate the study for reasons including, but not limited to: evidence that the PI or an involved investigator is unqualified to conduct research or fulfill sponsor responsibilities (eg, is listed on a debarment or ineligible investigator list); failure to meet timelines or achieve agreed upon milestones; a known or perceived risk to patient well-being is identified; or breach of contract. Additional grounds for termination are outlined in the IST
Agreement.
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9.4.2 publication of study results

Per the IST Agreement, the Investigator is required to submit to Pharmacyclics a copy of a planned publication (abstract, poster, oral presentation or manuscript) prior to the submission thereof for publication or disclosure. Pharmacyclics may provide scientific comments and suggestions understanding that the Investigator has sole editorial responsibility,and retains the authority to make the final determination on whether or not to incorporate Pharmacyclics comments or requests for additional information.
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9.5 follow-up

For subjects who complete or discontinue therapy, follow up assessments will not be performed, except to assess resolution of therapy-related toxicities that led to discontinuation of therapy.
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10 regulatory considerations 10.1institutional review

This clinical study was designed and will be implemented in accordance with the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local regulations
(including US Code of Federal Regulations [CFR] Title 21 and European Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. This protocol; the proposed informed consent; and all forms of information related to the study that will be provided to the subjects (eg, questionnaires, handouts, written instructions, diaries, advertisements used to recruit participants, etc)
will be submitted to and reviewed and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). Any changes made to the protocol will be submitted as a modification and will be approved by the IRB prior to implementation. The Protocol Director will disseminate the protocol amendment information to all participating investigators. The IRB must comply with current United States (US) regulations (§21 CFR 56) as well as country-specific national regulations and/or local laws. Per the IST Agreement, any amendments to the Protocol or Informed Consent Form must be sent to Pharmacyclics for review and approval prior to submission to the IRB. Written verification of IRB
approval will be obtained before any amendment is implemented. The following documents must be provided to Pharmacyclics or its authorized representative before entering subjects in this study: (1) a copy of the IRB letter that grants formal approval; and (2) a copy of the IRB-approved ICF.
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10.2protocol compliance and deviations 10.2.1

No deviation or changes from the procedures and process described by the IRB-approved protocol, except those necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s)
involves only logistical or administrative aspects of the trial [eg, change in study monitor(s), change of telephone number(s)], will be knowingly permitted without review and approval by the IRB.
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10.2.2 protocol deviations

Any deviation from the IRB-approved protocol, including those that eliminate an immediate hazard or are administrative nature, will be documented and explained in the study site file. In addition, any deviation from the approved protocol that meets the reporting requirements defined in the Stanford University HRPP Policy Guidance "Events and Information that Require Prompt Reporting to the IRB" GUI-P13 with be reported to the IRB within the defined timeframes.
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10.2.3 protected subject health information

Information on maintaining subject confidentiality in accordance to individual local and national subject privacy regulations must be provided to each subject as part of the informed consent process, either as part of the ICF or as a separate signed document (for example, in the US, a site-specific HIPAA
consent may be used). The Investigator or designee must explain to each subject that for the evaluation of study results, the subject's protected health information obtained during the study may be shared with Pharmacyclics and its designees, regulatory agencies, and IRBs. As the study Sponsor,
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e

Pharmacyclics will not use the subject's protected health information or disclose it to a third party without applicable subject authorization. It is the Investigator's or designee's responsibility to obtain written permission to use protected health information from each subject. If a subject withdraws permission to use protected health information, it is the Investigator's responsibility to obtain the withdrawal request in writing from the subject and to ensure that no further data will be collected from the subject. Any data collected on the subject before withdrawal will be used in the analysis of study results. During the review of source documents by the monitors or auditors, the confidentiality of the subject will be respected with strict adherence to professional standards and regulations.
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10.3data and safety monitoring plan

The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this study. The DSMC will audit study-related activities to determine whether the study has been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). This may include review of the following types of documents participating in the study: regulatory binders; case report forms; eligibility checklists; and source documents. In addition, the DSMC will regularly review serious adverse events and protocol deviations associated with the research to ensure the protection of human subjects. Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as needed.
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10.3.1 data management plan

CRFs will be used to collect the clinical study data and must be completed for each enrolled subject with all required study data accurately recorded such that the information matches the data contained in medical records (eg, physicians' notes, nurses' notes, clinic charts and other study-specific source documents). Authorized study site personnel (ie, listed on the Delegation of Authority log) will complete CRFs designed for this study according to the completion guidelines that will be provided. The Investigator will ensure that the CRFs are accurate, complete, legible, and completed within a reasonable time. At all times, the Investigator has final responsibility for the accuracy and authenticity of all clinical data. Study staff will be appropriately trained in the use of CRFs before the start of the study. After database lock, the Investigator will receive a copy of the subject data (eg, paper; CD; or other appropriate media) for archiving at the study site.
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10.3.1.1 record retention

The Investigator must keep a record that lists all subjects considered for enrollment (including those who did not undergo screening) in the study. For those subjects subsequently excluded from enrollment, the reason(s) for exclusion is to be recorded. The Investigator/study staff must maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. Essential documentation includes, but is not limited to, the IB, signed protocols and amendments, IRB approval letters (dated), signed Form FDA 1572 and Financial Disclosures, signed ICFs (including subject confidentiality information), drug dispensing and accountability records, shipping records of investigational product and study-related materials, signed, dated and completed CRFs, and documentation of CRF corrections, SAE forms and notification of SAEs and related reports, source documentation, normal laboratory values, curricula vitae for study staff, and all relevant correspondence and other documents pertaining to the conduct of the study.
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10.3.1.1 record retention

E
The Investigator must notify Pharmacyclics and obtain written approval from Pharmacyclics before destroying any clinical study documents or images (eg, scan, radiograph, ECG tracing) at any time. Should an Investigator wish to assign the study records to another party or move them to another location, advance written notice will be given to Pharmacyclics. Pharmacyclics will inform the Investigator of the date that study records may be destroyed or returned to Pharmacyclics.  
Pharmacyclics must be notified in advance of, and Pharmacyclics must provide express written approval of, any change in the maintenance of the foregoing documents if the Investigator wishes to move study records to another location or assign responsibility for record retention to another party. If the Investigator cannot guarantee the archiving requirements set forth herein at his or her study site for all such documents, special arrangements must be made between the Investigator and Pharmacyclics to store such documents in sealed containers away from the study site so that they can be returned sealed to the Investigator for audit purposes.
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10.4investigator responsibilities

A complete list of Investigator responsibilities is outlined in the clinical trial research agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the Investigator before commencement of the study. In summary, the Investigator will conduct the study according to the current protocol; will read and understand the IB; will obtain IRB approval to conduct the study; will obtain informed consent from each study participant; will maintain and supply to, auditors and regulatory agencies adequate and accurate records of study activity and drug accountability for study-related monitoring, audits, IRB reviews and regulatory inspections; will report SAEs to Pharmacyclics and IRB according to the specifics outlined in this protocol; will personally conduct or supervise the study; and will ensure that colleagues participating in the study are informed about their obligations in meeting the above commitments.
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10.5protocol amendments

Per the IST Agreement, any amendments to the Protocol or Informed Consent Form protocol must be sent to Pharmacyclics for review and approval prior to submission to the IRB. Written verification of IRB approval will be obtained before any amendment is implemented.
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10.6publication of study results

Per the IST Agreement, the Investigator is required to submit to Pharmacyclics a copy of a planned publication (abstract, poster, oral presentation or manuscript) prior to the submission thereof for publication or disclosure. Pharmacyclics may provide scientific comments and suggestions understanding that the Investigator has sole editorial responsibility, and retains the authority to make the final determination on whether or not to incorporate Pharmacyclics comments or requests for additional information.
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11 statistical considerations 11.1statistical design

This study uses the FDA approved dose of ibrutinib 420 mg PO daily for CLL/SLL and intra-patient dose-escalation of venetoclax to establish the efficacy, safety, and tolerability of venetoclax when combined with ibrutinib in patients with relapsed and refractory CLL/SLL. A description of the statistical methods to be used to analyze the efficacy and safety data is outlined below.
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11.2.1 primary endpoint

Complete response rate (CRR) 11.2.1.1 **Measurement Time Points** The time frame for assessment of the primary endpoint is 62 weeks.
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11.2.2 secondary endpoint(s)

Secondary Endpoints include:
- Overall response rate (ORR)
- Duration of response (DOR) - Time-to-progression (TTP)
- Progression-free survival (PFS)
- Overall survival (OS)
- Rate of minimal residual disease (MRD) negativity in the bone marrow
- Safety Efficacy analyses will be performed on the intent-to-treat population but will also detail the response rates for evaluable patients (those who receive at least one dose of venetoclax).
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11.2.2.1.1 assessment methods

Laboratory and clinical assessments gathered as directed in the Study Treatment Schedule (Section 9).
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11.2.2.2 overall response rate

The proportion of subjects with an overall response (per investigator assessment) will be calculated for all subjects based on IWCLL criteria.
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11.2.2.3 duration of response

Duration of response will be defined as the number of days from the date of first response per investigator assessment to the earliest recurrence or progressive disease per investigator assessment.  
If a subject is still responding then the subject's data will be censored at the date of the subject's last available clinical disease assessment. For subjects who never experienced response, the subject's data will be censored on the date of enrollment.
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11.2.2.4 time-to-progression

Time-to-progression will be defined as the number of days from the date of first dose (date of enrollment if not dosed) to the date of earliest disease progression (per the investigator assessment).  
All disease progression will be included regardless whether the event occurred while the subject was taking study drug or had previously discontinued study drug. If the subject does not experience disease progression, then the data will be censored at the date of the last available disease assessment.
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11.2.2.5 progression-free survival (pfs)

Progression-free Survival will be defined as the number of days from the date of first dose to the date of earliest disease progression (per the investigator assessment) or death. All disease progression will be included regardless whether the event occurred while the subject was taking study drug or had previously discontinued study drug. If the subject does not experience disease progression or death, then the data will be censored at the date of the last disease assessment.
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11.2.2.6 overall survival (os)

Overall survival will be defined as the number of days from the date of first dose to the date of death for all dosed subjects. For subjects who did not die, their data will be censored at the date of last study visit or the last known date to be alive, whichever is later.
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11.2.2.7 rate of minimal residual

MRD negativity will be defined as less than one CLL cell per 10,000 leukocytes (or below 10-4) on bone marrow-based flow cytometry. Rate of MRD negativity will be defined as the proportion of subjects who achieve MRD negativity status.
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11.2.3 exploratory endpoint(s) time to

Time to next anti-CLL treatment will be defined as the number of days from the date of the first dose of ibrutinib to the date of first dose of new non-protocol anti-leukemia therapy (NPT) or death from any cause. For subjects who did not take NPT, the data will be censored at the last known date to be free of NPT.
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11.4primary analysis 11.4.1 primary analysis

All enrolled subjects who receive at least one dose of ibrutinib will be included in the safety and response-evaluable populations.
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11.4.2 sample size

The total number of patients needed for this Phase 2 intra-patient dose escalation study is estimated to be 22, to accommodate 1 early withdrawal, and simultaneous screening of 2 eligible subjects for the last accrual slot. Accrual of 1 to 2 patients a month is anticipated. The historical rate of complete response (CR) in this setting is on the order of 7 to 8%.36 8% will be taken as a null hypothesis for an informal power calculation to describe the precision furnished by this study. With a minimum of 20 patients evaluable for CR, there is 80% power to reject a CR rate of 8% with a one-sided
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significance level of 5% if

Efficacy analysis will be performed on the intent-to-treat population but will also detail the response rates for evaluable patients (those who receive at least one dose of venetoclax).
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overall response rate

A 95% confidence interval based on binomial distribution will be constructed for the calculated ORR.
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duration of response

Duration of response will be analyzed by Kaplan-Meier methodology using data for all enrolled subjects. Median duration of response will be calculated and the corresponding 95% confidence interval will be presented.
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time-to-progression (ttp)

TTP will be analyzed by Kaplan-Meier methodology using data for all enrolled subjects. Median time TTP will be calculated and 95% confidence interval for median time TTP will be presented.
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progression-free survival

PFS will be analyzed by Kaplan Meier methodology using data for all dosed subjects. Median PFS
time will be calculated and 95% confidence interval for median PFS time will be presented.
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overall survival

OS will be analyzed by Kaplan-Meier methodology using data from all dosed subjects. Median time survival will be calculated and 95% confidence interval for the median time survival will be presented.
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rate of minimal residual disease

Ninety-five percent (95%) confidence intervals based on the binomial distribution will be provided.  
Time-to-Next Anti-CLL Treatment (TTNT) TTNT will be analyzed by Kaplan-Meier methodology using data for all dosed subjects. Median TTNT time will be calculated.
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11.4.4 safety analysis safety endpoints

- Frequency, severity, and relatedness of AEs - Frequency, severity and management of TLS - Frequency of AEs requiring discontinuation of study drug or dose reductions, or leading to death All patient safety information collected will be summarized using descriptive statistics (number of non-missing values, mean, median, standard deviation, minimum and maximum) for continuous variables and counts and percentages for categorical variables, where applicable. All safety outcome information reported will be presented in data listings.
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11.4.5 pharmacokinetic analysis

Values for the pharmacokinetic parameters for ibrutinib and venetoclax including the maximum observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) and AUC over a 24-hour dose interval (AUC0-24) will be determined using non-compartmental methods.  
Additional analyses may be performed if useful in the interpretation of the data.
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12 references

1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. *Blood*. 2006; 107: 265–76.  
2. Zwiebel JA, Cheson BD. Chronic lymphocytic leukemia: staging and prognostic factors.  
Semin *Oncol*. 1998;25(1):42-59.  
3. American Cancer Society: Cancer Facts and Figures *2013*. Atlanta, GA: American Cancer Society, 2013.  
4. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. *Blood*. 2010;116(19);3724-34. Erratum in: Blood. 2011;117(12):3477.  
5. Jemal A, Clegg LX, Ward E, et al. Annual report to the nation on the status of cancer, 1975-2001, with a special feature regarding survival. *Cancer*. 2004;101(1):3-27.  
6. Dighiero G, Maloum K, Desablens B, et al. Chlorambucil in indolent chronic lymphocytic leukemia.  
French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med. 1998;338:1506-14.  
7. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343:1750-7.  
8. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. *Blood*. 2005;105:49-53.  
9. Tam CS, O'Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. *Blood*. 2008;112:975-80.  
10. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. *Lancet*. 2010;376:1164-74.  
11. Bishop GA, Haxhinasto SA, Stunz LL, et al. Antigen-specific B-lymphocyte activation.  
Crit Rev *Immunol*. 2003;23:165–197.  
12. Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: The dark side of B-cell differentiation. Nat Rev *Immunol*. 2002;2:920–932.  
13. Afar DE, Park H, Howell BW, Rawlings DJ, Cooper J, Witte ON. Regulation of BTK by Src family tyrosine kinases. Mol Cell *Biol*. 1996;16:3465-71.  
14. Cheng G, Ye ZS, Baltimore D. Binding of Bruton's tyrosine kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated interaction. Proc Natl Acad Sci USA. 1994;91:8152-5.  
15. Humphries LA, Dangelmaier C, Sommer K, et al. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker. J Biol *Chem*. 2004;279:37651-61.  
16. Kuppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev *Cancer*. 2005;5:251-62. 17. Meeker T, Lowder J, Cleary ML, et al. Emergence of idiotype variants during treatment of B-cell lymphoma with anti-idiotype antibodies. N Engl J Med. 1985;312:1658-65.  
18. Gururajan M, Jennings CD, Bondada S. Cutting edge: constitutive B cell receptor signaling is critical for basal growth of B lymphoma. J *Immunol*. 2006;176:5715-9.  
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19. Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B cell development and function: a genetic perspective. Immunol Rev. 2000;175:120-127.  
20. Willis S, Day CL, Hinds MG, et al. The Bcl-2-regulated apoptotic pathway. J Cell Sci.  
2003;116(20):4053-6.  
21. Cory S, Adams JM. The Bcl-2 family: regulators of the cellular life-or-death switch.  
Nature Rev *Cancer*. 2002;2(9):647-56.  
22. Borner C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions.  
Mol *Immunol*. 2003;39(11):615-47.  
23. Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis.  
Oncogene. 2003;22(53):8590-607.  
24. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2.  
Proc Natl Acad Sci USA. 2005;102(39):13944-9.  
25. Calin GA, Cimmino A, Fabbri M, et al. MiR-15a and miR-16-1 cluster functions in human leukemia.  
Proc Natl Acad Sci USA. 2008;105(13):5166-71.  
26. Souers AJ, Leverson JD, Boghaert ER, et al. Venetoclax, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202-208.  
27. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin *Oncol*. 2006;24(19):3187-205 28. Yamamura K, Kamada S, Ito S, et al. Accelerated disappearance of melanocytes in bcl-2-deficient mice. *Cancer* Res. 1996;56(15):3546-50.  
29. Wilson H, O'Connor A, Czuczman S, et al. Phase 1/2a study of navitoclax (ABT-263) in relapsed or refractory lymphoid malignancies. *Haematologica*. 2010;95 Suppl 2:116-7. Abstract 0292.  
30. Yan W, Huang JX, Lax AS, et al. Overexpression of Bcl-W in the testis disrupts spermatogenesis:
revelation of a role of BCL-W in male germ cell cycle control. Mol *Endocrinol*. 2003;17(9):1868-79.  
31. Sugiyama N, Obinata M, Matsui Y. Bcl-2 inhibits apoptosis of spermatogonia and growth of spermatogonial stem cells in a cell-intrinsic manner. Mol Reprod Dev. 2001;58(1):30-8.  
32. Oldereid NB, Angelis PD, Wiger R, et al. Expression of Bcl-2 family proteins and spontaneous apoptosis in normal human testis. Mol Hum *Reprod*. 2001;7(5):403-8.  
33. Seymour JF, Davids MS, Pagel JM, et al. Bcl-2 inhibitor venetoclax (GDC-0199) monotherapy shows anti-tumor activity including complete remissions in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Presented at:
55th annual ASH Meeting; December 7-10, 2013; New Orleans, LA. Abstract 872.  
34. Pan Z, Scheerens H, Li SJ, et al. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. *ChemMedChem*. 2007;2:58-61.  
35. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. *Blood*. 2011;117:6287-96.  
36. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. *Blood*. 2015;125:2497-506.
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13 appendices 13.1appendix a. participant

The following Participant Eligibility Checklist will be completed in its entirety for each subject prior to registration. The completed, signed, and dated checklist will be retained in the patient's study file, and the study's Regulatory Binder. The Study Coordinator, treating Physician and an Independent Reviewer will verify that the participant's eligibility is accurate, complete, and legible in source records. A description of the eligibility verification process will be included in the EPIC or other Electronic Medical Record progress note.
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i. protocol information

| Protocol Title:         | An Open Label Phase 1-2 Trial of Venetoclax with Ibrutinib in Relapsed  and Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic  Leukemia   |
|-------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------|
| eProtocol Number:       | IRB-36705                                                                                                                                             |
| Principal Investigator: | Steven E Coutre, MD                                                                                                                                   |
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ii. subject information

Subject name / Study ID: Gender Male Female III. **Study Information** SRC-Approved IRB-Approved Contract signed
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iv. inclusion / exclusion criteria

| Inclusion Criteria               |                                                                                                                                                                                                                                                                                                    |    |                           |
|----------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|---------------------------|
| (From IRB-approved protocol 3.1) | Yes                                                                                                                                                                                                                                                                                                | No | Supporting Documentation* |
| 1.                               | Voluntarily sign and date an informed consent  form (ICF) with authorization to use protected  health information (in accordance with national and  local subject privacy regulations) and approved by  the Institutional Review Board (IRB) prior to  initiation of any study specific procedures |    |                           |
| 2.                               | Diagnosis of chronic lymphocytic leukemia CLL) or  small lymphocytic leukemia (SLL) meeting  IWCLL/NCI-WG criteria, and relapsed after or  refractory to at least 1 prior treatment                                                                                                                |    |                           |  
E  
| Steven E Coutre, MD              | Protocol 10691 dated 27 AUG 2020                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |    |                           |
|----------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|---------------------------|
| Inclusion Criteria               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |    |                           |
| (From IRB-approved protocol 3.1) | Yes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | No | Supporting Documentation* |
| 3.                               | Measurable nodal disease by computed  tomography (CT)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |    |                           |
| 4.                               | Adequate hematologic function independent of  transfusion and growth factor support for at least  7 days prior to screening [except for pegylated  G-CSF (pegfilgrastim) and darbepoetin which  require at least 14 days prior to screening] defined  as the following.  - Absolute neutrophil count > 750 cells/mm3  (0.75 x 109 /L) - Platelet count > 30,000 cells/mm3 (30 x 109 /L) without transfusion support; evidence of mucosal  bleeding; a known bleeding episode within  3 months of screening; or a history of a  bleeding disorder  - Hemoglobin > 8.0 g/dL If the bone marrow evaluation shows heavy  infiltration with underlying disease, growth factor  support may be administered after screening and  prior to the first dose of therapy. |    |                           |
| 5.                               | Adequate hepatic and renal function defined as: - Serum aspartate transaminase (AST) or alanine  transaminase (ALT) ≤ 2.5 x upper limit of normal  (ULN) - Estimated Creatinine Clearance ≥ 30 mL/min  (Cockcroft-Gault) - Bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due  to Gilbert's syndrome or of non-hepatic origin)                                                                                                                                                                                                                                                                                                                                                                                                                                |    |                           |
| 6.                               | PT/INR < 1.5 x ULN and PTT (aPTT) < 1.5 x ULN                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |    |                           |
| 7.                               | Men and women ≥ 18 years of age                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |    |                           |
| 8.                               | Eastern Cooperative Oncology Group (ECOG)  performance status of 0, 1, or 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |    |                           |
| 9.                               | Female subjects who are of non-reproductive  potential (ie, post-menopausal by history - no  menses for ≥ 1 year; OR history of hysterectomy;  OR history of bilateral tubal ligation; OR history of bilateral oophorectomy).  OR Female subjects of childbearing potential must  have a negative serum pregnancy test upon study  entry.                                                                                                                                                                                                                                                                                                                                                                                                                      |    |                           |  
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| Inclusion Criteria                                                                                                                                                                                                                                                                                                           |     |    |                           |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|----|---------------------------|
| (From IRB-approved protocol 3.1)                                                                                                                                                                                                                                                                                             | Yes | No | Supporting Documentation* |
| 10. Male and female subjects who agree to use highly  effective methods of birth control (eg, condoms,  implants, injectables, combined oral contraceptives,  some intrauterine devices [IUDs], sexual  abstinence, or sterilized partner) during the period  of therapy and for 90 days after the last dose of  study drug. |     |    |                           |  
| Exclusion Criteria               |                                                                                                                                                                                                                                                                                                                                                                                                                     |    |                           |
|----------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|---------------------------|
| (From IRB-approved protocol 3.2) | Yes                                                                                                                                                                                                                                                                                                                                                                                                                 | No | Supporting Documentation* |
| 1.                               | Prior treatment with either venetoclax or ibrutinib.                                                                                                                                                                                                                                                                                                                                                                |    |                           |
| 2.                               | Vaccinated with live, attenuated vaccine(s) within  28 days prior to first dose of study drug.                                                                                                                                                                                                                                                                                                                      |    |                           |
| 3.                               | Received an allogeneic stem cell transplant in the  past 1 year and must not have active cGVHD if  over 1 year post allogeneic transplant.                                                                                                                                                                                                                                                                          |    |                           |
| 4.                               | Richter's transformation confirmed by biopsy.                                                                                                                                                                                                                                                                                                                                                                       |    |                           |
| 5.                               | Active uncontrolled autoimmune cytopenias                                                                                                                                                                                                                                                                                                                                                                           |    |                           |
| 6.                               | Chemotherapy ≤ 21 days prior to first  administration of study treatment and/or  monoclonal antibody ≤ 4 weeks prior to first  administration of study treatment.                                                                                                                                                                                                                                                   |    |                           |
| 7.                               | History of other malignancies, except: - Malignancy treated with curative intent and with  no known active disease present for ≥ 3 years  before the first dose of study drug and felt to be  at low risk for recurrence by treating physician. - Adequately treated non-melanoma skin cancer or  lentigo maligna without evidence of disease. - Adequately treated carcinoma in situ without  evidence of disease. |    |                           |
| 8.                               | Concurrent systemic immunosuppressant therapy  (eg, cyclosporine A, tacrolimus, etc, or chronic  administration [> 14 days] of > 20 mg/day of  prednisone) within 28 days of the first dose of study  drug.                                                                                                                                                                                                         |    |                           |
| 9.                               | Recent infection requiring systemic treatment that  was completed ≤ 14 days before the first dose of  study drug.                                                                                                                                                                                                                                                                                                   |    |                           |  
E  
| Steven E Coutre, MD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Protocol 10691 dated 27 AUG 2020   |    |                           |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|----|---------------------------|
| Exclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                    |    |                           |
| (From IRB-approved protocol 3.2)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Yes                                | No | Supporting Documentation* |
| 10. Unresolved toxicities from prior anti-cancer therapy,  defined as having not resolved to Common  Terminology Criteria for Adverse Event (CTCAE,  version 4.03), Grade ≤ 1, or to the levels dictated in  the inclusion/exclusion criteria except for alopecia. 11. Known bleeding disorders (eg, von Willebrand's  disease) or hemophilia 12. History of stroke or intracranial hemorrhage within  6 months prior to first dose of study drug. 13. Known history of human immunodeficiency virus  (HIV) or active with hepatitis C virus (HCV) or  hepatitis B virus (HBV).  Subjects who are positive for hepatitis B core  antibody or hepatitis B surface antigen must have a  negative polymerase chain reaction (PCR) result  before enrollment. Those who are PCR-positive  will be excluded. 14. Any uncontrolled active systemic infection. 15. Major surgery within 4 weeks of first dose of study  drug 16. Any life-threatening illness, medical condition, or  organ system dysfunction that, in the investigator's  opinion, could compromise the subject's safety or  put the study outcomes at undue risk. 17. Currently active, clinically significant cardiovascular  disease, such as uncontrolled arrhythmia or Class  3 or 4 congestive heart failure as defined by the  New York Heart Association Functional  Classification; or a history of myocardial infarction,  unstable angina, or acute coronary syndrome  within 6 months screening. 18. Unable to swallow capsules; malabsorption  syndrome; disease significantly affecting  gastrointestinal function; resection of the stomach  or small bowel; symptomatic inflammatory bowel  disease or ulcerative colitis; or partial or complete  bowel obstruction 19. Concomitant use of warfarin or other Vitamin K  antagonists 20. Received a strong cytochrome P450 (CYP) 3A  inhibitor or inducer within 7 days prior to the first  dose of ibrutinib, OR subjects who require  continuous treatment with a strong  cytochrome P450 CYP3A inhibitor or inducer  (see Appendix C) |                                    |    |                           |  
| Exclusion Criteria                                                                                                                                                                                                                                                          |     |    |                           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|----|---------------------------|
| (From IRB-approved protocol 3.2)                                                                                                                                                                                                                                            | Yes | No | Supporting Documentation* |
| 21. Lactating or pregnant. 22. Unwilling or unable to participate in all required  study evaluations and procedures. 23. Unable to understand the purpose and risks of the  study  24. Subjects with chronic liver disease with hepatic  impairment Child-Pugh class B or C |     |    |                           |  
* All subject files must include supporting documentation to confirm subject eligibility. The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record review.  
By signing this form of this trial I verify that this subject is: eligible / ineligible for participation in the study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as required by Stanford School of Medicine's Research Management Group. Treating Physician Signature: Date:
Printed name:  
| Secondary Reviewer Signature:   | Date:   |
|---------------------------------|---------|
| Printed name:                   |         |  
| Study Coordinator Signature:   | Date:   |
|--------------------------------|---------|
| Printed name:                  |         |  
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13.2appendix b. ecog status scores

| Status                                                                                            | Eastern Cooperative Oncology Group (ECOG) Performance Status**                                                                                           |
|---------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                 | Fully active, able to carry on all pre-disease performance without restriction.                                                                          |
| 1                                                                                                 | Restricted in physically strenuous activity but ambulatory and able to carry out work of a  light or sedentary nature, eg, light housework, office work. |
| 2                                                                                                 | Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and  about more than 50% of waking hours.                       |
| 3                                                                                                 | Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.                                                               |
| 4                                                                                                 | Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.                                                                    |
| 5                                                                                                 | Dead.                                                                                                                                                    |
| **Oken,MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern Cooperative |                                                                                                                                                          |  
**Oken,MM, Creech RH, Tormey DC, et al. *Toxicity And Response Criteria Of The Eastern Cooperative* Oncology Group. Am J Clin *Oncol*. 1982;5:649-655.  
Available at: http://www.ecog.org/general/perf_stat.html. Accessed 4 January 2008.
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13.3appendix c. inhibitors and inducers

Inhibitors and inducers of CYP3A are defined as follows.  
Note that this is not an exhaustive list. Further information can be found at the following websites: http://medicine.iupui.edu/clinpharm/ddis/main-table/ and http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe ling/ucm080499.htm Refer to Section 4.3.3.1 on instructions for concomitant use of CYP3A inhibitors and inducers with ibrutinib and venetoclax.  
| CYP3A inhibitors:   |                     |              |
|---------------------|---------------------|--------------|
| Strong              | Moderate            | Weak         |
| boceprevir          | aprepitant          | alprazolam   |
| clarithromycin      | amprenavir          | amiodarone   |
| cobicistat          | atazanavir          | amlodipine   |
| conivaptan          | ciprofloxacin       | atorvastatin |
| indinavir           | crizotinib          | bicalutamide |
| itraconazole        | darunavir/ritonavir | cilostazol   |
| ketoconazole        | dronedarone         | cimetidine   |
| lopinavir           | erythromycin        | cyclosporine |
| mibefradil          | diltiazem           | fluvoxamine  |
| nefazodone          | fluconazole         | fluoxetine   |  
E  
| Steven E Coutre, MD             | Protocol 10691 dated 27 AUG 2020                             |                                     |
|---------------------------------|--------------------------------------------------------------|-------------------------------------|
| CYP3A inhibitors:               |                                                              |                                     |
| Strong                          | Moderate                                                     | Weak                                |
| nelfinavir                      | fosamprenavir                                                | ginkgo                              |
| posaconazole                    | imatinib                                                     | goldenseal                          |
| ritonavir                       | verapamil                                                    | isoniazid                           |
| saquinavir                      | nilotinib                                                    |                                     |
| telaprevir                      | oral contraceptives                                          |                                     |
| telithromycin                   | pazopanib                                                    |                                     |
| troleandomycin                  | ranitidine                                                   |                                     |
| voriconazole*                   | ranolazine suboxone tipranavir/ritonavir ticagrelor zileuton |                                     |
| CYP3A inducers:                 |                                                              |                                     |
| Strong                          | Moderate                                                     | Weak                                |
| avasimibe                       | bosentan                                                     | amprenavir                          |
| carbamazepine                   | efavirenz                                                    | aprepitant,                         |
| phenobarbital                   | etravirine                                                   | armodafinil                         |
| phenytoin                       | modafinil                                                    | clobazamechinacea                   |
| rifabutin                       | nafcillin                                                    | glucocorticoids (eg, prednisone)    |
| rifampin                        | oxcarbazepine                                                | nevirapine                          |
| St John's Wort                  | troglitazone                                                 | pioglitazone rufinamide vemurafenib |
| Substrates of P-gp              |                                                              |                                     |
| aliskiren                       | fexofenadine                                                 | saxagliptin                         |
| ambrisentan                     | lapatinib                                                    | sirolimus                           |
| colchicines                     | loperamide                                                   | sitagliptin                         |
| dabigatran etexilate            | maraviroc                                                    | talinolol                           |
| digoxin                         | nilotinib                                                    | tolvaptan                           |
| everolimus                      | ranolazine                                                   | topotecan                           |
| Inhibitors of P-gp (Venetoclax) |                                                              |                                     |
| amiodarone                      | cyclosporine                                                 | quinidine                           |
| azithromycin                    | dronedarone                                                  | ranolazine                          |
| captopril                       | felodipine                                                   | ticagrelor                          |
| carvedilol                      | quercetin                                                    |                                     |  
E  
| BCRP (Venetoclax only)                                                                                                                                                       |                              |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|
| Substrates                                                                                                                                                                   | Inhibitors                   |
| methotrexate                                                                                                                                                                 | cyclosporine                 |
| mitoxantrone                                                                                                                                                                 | geftinib                     |
| irrinotecan lapatinib rosuvastatin sulfasalazine topotecan                                                                                                                   | OATP1B1/B3 (Venetoclax only) |
| Substrates                                                                                                                                                                   | Inhibitors                   |
| atrasentan                                                                                                                                                                   | gemfibrozil                  |
| atorvastatin                                                                                                                                                                 | eltrombopag                  |
| ezetimibe                                                                                                                                                                    | cyclosporine                 |
| fluvastatin                                                                                                                                                                  | tipranavir                   |
| glyburide olmesartan rosuvastatin simvastatin acid pitavastatin pravastatin repaglinide telmisartan valsartan * Allowed to dose with 140 mg ibrutinib based on clinical data |                              |  
Steven E Coutre, MD  
| 13.4 Appendix D.  Modified 2008 IWCLL Criteria for Tumor Response   |                         |                        |                         |                |
|---------------------------------------------------------------------|-------------------------|------------------------|-------------------------|----------------|
| Partial Remission                                                   |                         |                        |                         |                |
| (PR) at Least                                                       |                         |                        |                         |                |
| 2 Criteria from                                                     | Progressive Disease     |                        |                         |                |
| Group A AND at                                                      | (PD) at Least           |                        |                         |                |
| Complete Remission                                                  | Least 1 Criterion       | 1 Criterion from Group | Stable Disease          |                |
| (CR) All Criteria                                                   | from Group B            | A OR 1 Criterion from  | (SD) All Criteria       |                |
| Parameter                                                           | Must be Met'            | Must be Met            | Group B Must be Met     | Must be Met    |
| Group A                                                             |                         |                        |                         |                |
| Lymphadenopathy                                                     | None > 1.5 cm           | Decrease > 50%         | Increase > 50% a or any | Change of –49% |
| nw LN > 1.5 cm                                                      | to +49%                 |                        |                         |                |
| Blood                                                               | < 4000/µL               | Decrease > 50%         | Increase ≥ 50% over     | Change of –49% |
| from baseline                                                       | baseline ( ≥ 5000/µL)   | to +49%                |                         |                |
| Lymphocytes                                                         |                         |                        |                         |                |
| Hepatomegaly                                                        | None                    | Decrease > 50%         | Increase ≥ 50%          | Change of –49% |
| to +49%                                                             |                         |                        |                         |                |
| Splenomegaly                                                        | None                    | Decrease > 50%         | Increase ≥ 50%          | Change of –49% |
| to +49%                                                             |                         |                        |                         |                |
| Normocellular,                                                      | N/A                     | N/A                    | N/A                     |                |
| Marrow                                                              | v                       | 30% lymphocytes,       |                         |                |
| n B lymphoid                                                        |                         |                        |                         |                |
| nodules; hypocellular                                               |                         |                        |                         |                |
| marrow defines CRi                                                  |                         |                        |                         |                |
| Group B                                                             |                         |                        |                         |                |
| Platelet Count                                                      | > 100,00/µµ             | > 100,000/µL or        | Decrease of > 50% from  | Change of –49% |
| increase > 50%                                                      | baseline secondary to   | to +49%                |                         |                |
| over baseline                                                       | CL                      |                        |                         |                |
| Hemoglobin                                                          | > 11.0 g/dL h           | > 11.0 g/dL or         | Decrease of > 2 g/dL    | Increase to    |
| increase ≥ 50%                                                      | from baseline secondary | ≤ 11.0 g/dL over       |                         |                |
| over baseline                                                       | to CLL                  | baseline, or           |                         |                |
| decrease < 2 g/dL                                                   |                         |                        |                         |                |
| Neutrophils                                                         | > 1500/µL h             | > 1500/µL or           | Decrease ≥ 50% from     | N/A            |
| increase > 50%                                                      | baseline secondary to   |                        |                         |                |
| over baseline                                                       | CL                      |                        |                         |                |
| Other Considerations                                                |                         |                        |                         |                |
| New Lesions                                                         | None                    | None                   | Appearance of new       | None           |
| palpable lymph nodes                                                |                         |                        |                         |                |
| (> 1.5 cm in longest                                                |                         |                        |                         |                |
| diameter) or any new                                                |                         |                        |                         |                |
| extra nodal lesion                                                  |                         |                        |                         |                |
| (regardless of size) or                                             |                         |                        |                         |                |
| transformation to a more                                            |                         |                        |                         |                |
| aggressive histology,                                               |                         |                        |                         |                |
| e.g., Richter Syndrome                                              |                         |                        |                         |                |  
Steven E Coutre, MD
Protocol 10691 dated 27 AUG  2020  
| Partial Remission                                                                                        |                      |                        |                         |                  |
|----------------------------------------------------------------------------------------------------------|----------------------|------------------------|-------------------------|------------------|
| (R) at Least                                                                                             |                      |                        |                         |                  |
| 2 Criteria from                                                                                          | Progressive Disease  |                        |                         |                  |
| Group A AND at                                                                                           | (PD) at Least        |                        |                         |                  |
| Complete Remission                                                                                       | Least 1 Criterion    | 1 Criterion from Group | Stable Disease          |                  |
| (R) All Criteria                                                                                         | from Group B         | A OR 1 Criterion from  | (SD) All Criteria       |                  |
| Parameter                                                                                                | Must be Met a        | Must be Met            | Group B Must be Met     | Must be Met      |
| Other Considerations                                                                                     |                      |                        |                         |                  |
| Non-Target                                                                                               | Nodes must be        | No                     | Unequivocal progression | No change or     |
| Lesions                                                                                                  | normal size as       | change/decreased       | decrease or             |                  |
| visually estimated;                                                                                      | n-substantial        |                        |                         |                  |
| extra nodal and other                                                                                    | increase             |                        |                         |                  |
| assessable disease                                                                                       |                      |                        |                         |                  |
| should be absent                                                                                         |                      |                        |                         |                  |
| Target Extra                                                                                             | Absence of any extra | > 50% decrease in      | > 50% increase in the   | Not CR, CRi, PR, |
| Nodal Disease                                                                                            | ndal disease by      | SPD                    | longest diameter of any | or SD            |
| physical examination                                                                                     | extra nodal lesion   |                        |                         |                  |
| (palpable, visualized                                                                                    |                      |                        |                         |                  |
| extra nodal) and CT                                                                                      |                      |                        |                         |                  |
| scan                                                                                                     |                      |                        |                         |                  |
| CLL = chronic lymphocytic leukemia; LN = lymph nodes; N/A = Not applicable; SPD = sum of the products of |                      |                        |                         |                  |  
diameters; CRi = complete remission with incomplete marrow recovery a.  
CR also requires the lack of disease-related constitutional symptoms.  
b.  
Transformation to a more aggressive histology (e.g., Richter Syndrome) would also qualify as a PD.  
C.  
Sum of the products of multiple LNs (as evaluated by CT scans).  Note in eCRF if by physical examination only.  
d.  
Increase in SPD of multiple nodes, or in greatest diameter of any previous site, or appearance of any new lymphadenopathy or organomegaly.  Degree of change in LN or lymphocyte counts should be measured from nadir
(lowest post-treatment) values.  
e.  
f.  
Sum products of up to 6 LNs or LN masses (target lesions), with no increase in an LN or new enlarged LN.  
Increase of < 25% in small LNs (< 2 cm) not significant.  Decreases should be measured compared to baseline (pre-treatment) values.  
If enlarged before therapy.  
g An increase in the previously noted enlargement of the liver or spleen by 50% or more or the de novo appearance of hepatomegaly or splenomegaly.  
h.  
Without the need for exogenous growth factors or transfusions.
8 correlative / special studies
13.5 appendix e. recommendations for

Within the first 24 hours after either the first dose or dose escalation, if any laboratory criteria below
.  
are met, the patient should be hospitalized for monitoring and the investigator notified.  No additional venetoclax doses should be administered until resolution. A rapidly rising serum potassium is a medical emergency.  
- Nephrology (or other acute dialysis service) must be consulted/contacted (per institutional standards to ensure emergency dialysis is available) upon admission for any subject hospitalized prophylactically or in response to laboratory changes.  
- IV fluids (eg, D5 1/2 normal saline) should be initiated at a rate of at least 1 mL/kg/hr rounded to the nearest 10 mL (target 150 to 200 mL/hr; not < 50 mL/hr). Modification of fluid rate should also be considered for individuals with specific medical needs.  
- Monitor for symptoms or signs of TLS (eg, fever, chills, tachycardia, nausea, vomiting, diarrhea, diaphoresis, hypotension, muscle aches, weakness, paresthesias, mental status changes, confusion and seizures). If any clinical features are observed, recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT.  
- Vital signs should be taken at time of all blood draws or any intervention. - The management recommendations below focus on the minimum initial responses required. If a diagnosis of TLS is established, ongoing intensive monitoring and multi-disciplinary management will be per institutional protocols.  
In addition to the recommendations below, for patients receiving the first dose of venetoclax:
- For potassium increase ≥ 0.5 mmol/L from baseline, or any value > 5.0 mmol/L, recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT and follow first guideline.  
- For phosphorus increase of > 0.5 mg/dL AND > 4.5 mg/dL, administer phosphate binder and recheck potassium, phosphorus, uric acid, calcium and creatinine within 1 hour STAT.
8 correlative / special studies
if potassium >= 0.5 mmol/l

Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. If further ≥ 0.2 mmol/L increase in potassium, but still < upper limit of normal (ULN), manage as per potassium ≥ ULN. Otherwise recheck in 1 hour. Resume per protocol testing if change in potassium is < 0.2 mmol/L,
and potassium < ULN, and no other evidence of tumor lysis.  
At the discretion of the investigator, may recheck prior to hospitalization. If stable or decreased, and still WNL, hospitalization is at the discretion of the investigator. Potassium, phosphorus, uric acid, calcium and creatinine must be rechecked within 24 hours.
8 correlative / special studies
if potassium > upper limit

Perform STAT ECG and commence telemetry. Nephrology (or other acute dialysis service) notification with consideration of initiating dialysis. Administer Kayexalate 60 g (or Resonium A 60 g). Administer furosemide 20 mg IV × 1. Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is ECG/telemetry evidence of life threatening arrhythmias. Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. If potassium < ULN 1 hour later, repeat potassium, phosphorus, uric acid, calcium and creatinine 1, 2 and 4 hours, if no other evidence of tumor lysis.  
If Potassium ≥ 6.0 mmol/L(6.0 mEq/L) and/or symptomatic (eg, muscle cramps, weakness, paresthesias, nausea, vomiting, diarrhea)
Perform STAT ECG and commence telemetry. Nephrology (or other acute dialysis service) assessment with consideration of initiating dialysis. Administer Kayexalate 60 g (or Resonium A 60 g). Administer furosemide 20 mg IV × 1. Administer insulin 0.1 U/kg IV + D25 2 mL/kg IV. Administer sodium bicarbonate 1 to 2 mEq/kg IV push.  
If sodium bicarbonate is used, rasburicase should not be used as this may exacerbate calcium phosphate precipitation. Administer calcium gluconate 100 to 200 mg/kg IV slowly if there is ECG/telemetry evidence of life threatening arrhythmias. Do not administer in same IV line as sodium bicarbonate. Recheck potassium, phosphorus, uric acid, calcium and creatinine every hour STAT.
8 correlative / special studies
if uric acid >= 8.0

Consider rasburicase (dose based on local guidelines and/or institutional standards). If rasburicase is used, sodium bicarbonate should not be used as this may exacerbate calcium phosphate precipitation. Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT.  
If Uric acid ≥ 10 mg/dL (595 μmol/L) OR Uric acid ≥ 8.0 mg/dL(476 μmol/L) with 25% increase and
8 correlative / special studies
creatinine increase >= 0.3 mg/dl

Administer rasburicase (dose based on local guidelines and/or institutional standards). When rasburicase is used, sodium bicarbonate should not be used as this may exacerbate calcium phosphate precipitation. Notify nephrology (or other acute dialysis service). Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. If uric acid < 8.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric acid, calcium and creatinine 2 and 4 hours, later, if no other evidence of tumor lysis.  
If Calcium ≤ 7.0 mg/dL (1.75 mmol/L) AND Patient symptomatic (eg, muscle cramps, hypotension, tetany, cardiac arrhythmias)
Administer calcium gluconate 50 to 100 mg/kg IV slowly with ECG monitoring. Telemetry. Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. If calcium normalized 1 hour later, repeat potassium, phosphorus, uric acid, calcium and creatinine 2 and 4 hours, later, if no other evidence of tumor lysis. Calculate corrected calcium and check ionized calcium if albumin low.
8 correlative / special studies
if phosphorus >= 5.0 mg/dl

Administer a phosphate binder (eg, aluminum hydroxide, calcium carbonate, sevelamer hydroxide, or lanthanum carbonate). Nephrology (or other acute dialysis service) notification (dialysis required for phosphorus ≥ 10 mg/dL). Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 hour STAT. If phosphorus < 5.0 mg/dL 1 hour later, repeat potassium, phosphorus, uric acid, calcium and creatinine 2 and 4 hours, later, if no other evidence of tumor lysis.
8 correlative / special studies
if creatinine increase >= 25%

Start or increase rate of IV fluids. Recheck potassium, phosphorus, uric acid, calcium and creatinine in 1 to 2 hours STAT.
8 correlative / special studies
section 2 ongoing dosing of

Management of electrolyte changes from last value at intervals > 24 hours after either the first dose or dose escalation (eg, 48 or 72 hours) are as below.  
Note: If the patient is hospitalized, no additional venetoclax doses should be administered until resolution.  
- For potassium, admit patient for any increase ≥ 1.0 mmol/L (1.0 mEq/L), or any level > upper limit of normal. o Refer to the management guidelines for electrolyte changes observed within the first 24 hours after either the first dose or dose escalation (see prior section).  
- If a smaller potassium increase is observed that does not meet the criteria for admission above, recheck potassium, phosphorus, uric acid, calcium and creatinine in 24 hours and confirm no evidence of tumor lysis prior to further venetoclax dosing.  
- For uric acid, calcium, phosphorus and creatinine, refer to the management guidelines for electrolyte changes observed within the first 24 hours after either the first dose or dose escalation (see prior table).
Steven E Coutre, MD