ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).

TPS7566 Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 106 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.

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Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL

Blood ◽

10.1182/blood.2021011895 ◽

2021 ◽

Author(s):

Tanya Siddiqi ◽

Jacob D Soumerai ◽

Kathleen A Dorritie ◽

Deborah M. Stephens ◽

Peter A Riedell ◽

...

Keyword(s):

T Cells ◽

High Risk ◽

Residual Disease ◽

Phase 1 ◽

Lymphocytic Leukemia ◽

T Cell Therapy ◽

Car T Cells ◽

Car T ◽

Grade 3 ◽

Dose Levels

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50×106 or 100×106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2‒11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100×106 CAR+ T cells.

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Combination Chemoimmunotherapy with Pentostatin, Cyclophosphamide and Rituximab Shows Significant Clinical Activity with Low Accompanying Toxicity in Previously Untreated B-Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v108.11.35.35 ◽

2006 ◽

Vol 108 (11) ◽

pp. 35-35

Author(s):

Neil Kay ◽

Susan Geyer ◽

Timothy Call ◽

Tait Shanafelt ◽

Clive Zent ◽

...

Keyword(s):

Flow Cytometry ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Residual Disease ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Hematologic Toxicity ◽

Free Survival ◽

Significant Clinical Activity

Abstract BACKGROUND: B-Chronic Lymphocytic Leukemia (CLL) is still uncurable but very powerful new tools are available with the use of chemoimmunotherapy (CIT). Purine nucleoside-based regimens that incorporate rituximab have generated very high levels of overall responses (OR) with significant percentage of those complete responses (CR) in previously untreated CLL. Here we report and update our experience with a phase 2 pentostatin-based CIT regimen for previously untreated CLL as conducted at 2 medical centers. We also studied the association of outcome based on risk stratification parameters and achievement of minimal residual disease. METHODS: Building on prior work of pentostatin in CLL by us (Kay ASH, 2004) and others, we initiated a trial of combined pentostatin (P)(2 mg/m2), cyclophosphamide (C)(600 mg/m2) and rituximab (R)(375 mg/m2) for symptomatic, previously untreated patients (n=65). This PCR regimen is given on a 21-day, 6-cycle schedule. However, the initial cycle of treatment uses thrice weekly rituximab as described by us earlier. In brief, this was rituximab at 100 mg/m2 on day 1, 375 mg/m2 on days 3 and 5 of the first week only. Prophylactic Sulfamethoxazole/Trimethoprim and Acyclovir were given to all patients for 1 year starting on the first cycle of therapy with PCR. All patients were risk stratified using CD38, ZAP-70, immunoglobulin heavy chain variable region gene (IgVH) and FISH panel assessments at entry. RESULTS: These patients were characterized as mostly in high-risk categories. Of 64 evaluable patients, 34 (53%) were high Rai risk (stage 3–4), 71% were non mutated for the IgVH gene, 34% were CD38+ and 34% were ZAP-70+. Thirty patients (52%) had one FISH anomaly, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs, and no major infections. NCI Working Group Criteria Responses occurred in 58 (91%) with 26 (41%) complete responses (CR), 14 (22%) nodular partial responses (nodular PR), and 18 (28%) partial responses (PR) patients. Outcome for all 64 patients demonstrates a median progression-free survival of 32.6 months. Importantly, no high risk factor (i.e., age, FISH, IgVH status, CD38+, ZAP-70+) except for del (17p) defect (n=3) precluded attaining a CR or NPR. In contrast, we found this regimen was equally effective in young vs. elderly (>70 yrs) patients and in del(11)(q22.3) vs. other favorable prognostic FISH factors. Examination of outcome among CR and nodular PR patients for PFS by flow cytometry status (negative vs. positive, i.e., ≤ 1 % CD5+/CD19+ vs. ≥ 1 % CD5+/CD19+) demonstrated improvement in progression free survival for patients who attained flow cytometry negativity (p = 0.009). Conclusion: This novel regimen of pentostatin, cyclophosphamide and rituximab for previously untreated CLL demonstrated significant clinical activity despite poor risk-based prognoses with minimal toxicity in terms of bone marrow suppression and/or infections. The additional feature of this approach is the ability to have durable responses for all age groups and even CLL patients with a del(11)(q22.3).

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Phase 1/2 study of safety/efficacy using trabectedin, ipilimumab, and nivolumab as first-line treatment of advanced soft tissue sarcoma (STS).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.5_suppl.tps46 ◽

2018 ◽

Vol 36 (5_suppl) ◽

pp. TPS46-TPS46 ◽

Cited By ~ 2

Author(s):

Erlinda Maria Gordon ◽

Victoria S. Chua-Alcala ◽

Katherine Kim ◽

William W. Tseng ◽

Doris M Quon ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Phase 1 ◽

Objective Response ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Categorical Variables ◽

Phase 2 ◽

First Line ◽

First Line Therapy ◽

Number Of Patients

TPS46 Background: Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them. Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: (1) To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS, (2) To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) , and (3) To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors. Methods: Forty patients ≥18 years of age with advanced STS will be enrolled. This is a phase 1/2 study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II. Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. Statistical Considerations: NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. Clinical trial information: NCT 03138161.

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Phase I/II study of avadomide (CC-122) in combination with R-CHOP for newly diagnosed DLBCL.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3501 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3501-3501

Author(s):

Neha Mehta-Shah ◽

Julio C. Chavez ◽

Pau Abrisqueta ◽

Nathalie Johnson ◽

Juan Miguel Bergua Burgues ◽

...

Keyword(s):

High Risk ◽

Phase 1 ◽

Prognostic Score ◽

Objective Response ◽

Survival Rates ◽

Dose Intensity ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Complete Response ◽

Newly Diagnosed

3501 Background: In certain subsets of patients (pts) with diffuse large B-cell lymphoma (DLBCL), the failure rate of standard R-CHOP treatment is high. Pts with high-risk disease (International Prognostic score [IPI] 3-5) have a particularly poor prognosis, with 3-y survival rates of ~62% with R-CHOP alone. The cereblon E3 ligase modulator avadomide (CC-122) showed activity in pts with relapsed or refractory DLBCL. We report results of avadomide plus R-CHOP in previously untreated pts with high-risk DLBCL. Methods: CC-122-DLBCL-002 (NCT03283202) is a phase 1/2 study of avadomide plus R-CHOP-21 in pts newly diagnosed with DLBCL not otherwise specified with IPI scores 3-5 who were aged ≥18 y. Pts received standard R-CHOP and escalating doses (1-3 mg) of oral avadomide for up to six 21-d cycles (Table). All pts received pegfilgrastim support. Primary objectives were to assess safety, tolerability, and complete response (CR) rate. Secondary objectives include evaluation of additional efficacy parameters (objective response rate [ORR], progression-free survival [PFS], and overall survival) and biomarkers. Results: As of July 30, 2019, 35 pts were enrolled in the phase 1 part of the study. Median age was 66 y (range, 20-75), 23 pts (66%) were aged > 60 y, 18 (51%) had an IPI score of 3, and 17 (49%) had an IPI score of 4-5. Thirty-two pts (91%) completed 6 cycles of treatment. Median relative total dose intensity of avadomide was 99% and the average relative dose intensity of R-CHOP was 95%. Six pts had dose-limiting toxicities: 1 pt had neutropenia and bacterial hepatic infection; 1 had pneumonia; 1 had febrile neutropenia (FN); 1 had FN and hypotension; 1 had FN due to skin infections; and 1 had sepsis. The recommended phase 2 dose was 3 mg 2/3 wk. Grade 3/4 adverse events in ≥10% of pts were neutropenia (54%), anemia (20%), leukopenia (20%), lymphopenia (14%), hypophosphatemia (14%), and FN (11%). Among 34 efficacy-evaluable pts, the ORR was 88% (n = 30/34), including a CR rate of 79% (n = 27/34) at the end of treatment. With a median follow-up of 10 mo, the 1-y PFS rate was 80% (95% CI, 58-92). Correlative analyses will be presented at the meeting. Conclusions: Avadomide plus R-CHOP was well-tolerated with no significant additive toxicities. The promising efficacy in this high-risk pt population warrants further evaluation of immunomodulatory drugs combined with immunochemotherapy for pts with previously untreated DLBCL. Clinical trial information: NCT03283202 . [Table: see text]

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Phase 1 clinical trial of the PI3Kδ inhibitor YY-20394 in patients with B-cell hematological malignancies

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01140-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Bo Jiang ◽

Junyuan Qi ◽

Yuqin Song ◽

Zengjun Li ◽

Meifeng Tu ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Phase 1 ◽

Objective Response ◽

Human Study ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Lymphocytic Leukemia ◽

Pharmacokinetic Parameters ◽

Durable Response

AbstractYY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20–200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted.Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1.

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Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7555 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7555-7555

Author(s):

Sattva Swarup Neelapu ◽

Caron A. Jacobson ◽

Olalekan O. Oluwole ◽

Javier Munoz ◽

Abhinav Deol ◽

...

Keyword(s):

T Cell ◽

Phase 1 ◽

Objective Response ◽

B Cell Lymphoma ◽

Phase 2 ◽

T Cell Therapy ◽

Car T Cell ◽

Car T ◽

Grade 3

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.

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Fixed-duration (FD) first-line treatment (tx) with ibrutinib (I) plus venetoclax (V) for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of the FD cohort of the phase 2 captivate study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7501-7501

Author(s):

Paolo Ghia ◽

John N. Allan ◽

Tanya Siddiqi ◽

Thomas J. Kipps ◽

Ryan Jacobs ◽

...

Keyword(s):

High Risk ◽

Tp53 Mutation ◽

Residual Disease ◽

Tumor Lysis Syndrome ◽

Lymphocytic Leukemia ◽

Fixed Duration ◽

Phase 2 ◽

First Line ◽

Primary Analysis ◽

Color Flow

7501 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line I+V in CLL. We previously reported results from the Minimal Residual Disease (MRD) cohort wherein undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of I+V, and 30-mo PFS rates were ≥95% irrespective of subsequent randomized treatment (Wierda, ASH 2020). We now present results from the FD cohort, evaluating fixed-duration tx with I+V. Methods: Pts aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Primary endpoint was CR rate, including CR with incomplete recovery (CRi); secondary endpoints were ORR, duration of response, uMRD rate (<10-4 by 8-color flow cytometry), PFS, OS, tumor lysis syndrome (TLS) risk reduction, and adverse events (AEs). Results: 159 pts were enrolled (median age 60 y). High-risk features included del(17p)/ TP53 mutation, 17%; del(11q), 18%; complex karyotype, 19%; and unmutated IGHV, 56%. 147 (92%) and 149 (94%) pts completed planned tx with I and V, respectively. Median time on study was 27.9 mo (range, 0.8–33.2). With fixed-duration I+V, CR rate was 55% (95% CI 48–63) in the overall population and was consistent across high-risk subgroups. Of the 88 pts who achieved CR, 78 (89%) had durable CR (duration ≥1 y); 1 died 7 mo after CR, and 9 with <1 y follow-up were not evaluable. ORR was 96%. Best uMRD response was achieved in 77% of pts in peripheral blood (PB) and 60% of pts in bone marrow (BM). 24-mo PFS was 95%; 24-mo OS was 98%. Results were similar in pts without del(17p) (n=136) (Table). In pts with del(17p)/ TP53 mutation (n=27), CR rate was 56%, uMRD rate was 81% (PB) and 41% (BM), and 24-mo PFS was 84% (95% CI 63–94). Of 34 pts with high baseline TLS risk based on tumor burden, 32 (94%) shifted to medium or low risk after I lead-in; no TLS occurred. AEs were primarily grade 1/2. Most common grade 3/4 AEs were neutropenia (33%), hypertension (6%), and neutrophil count decreased (5%). AEs led to discontinuation of I in 4% and V in 2%. Conclusions: First-line I+V is an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides deep, durable responses in pts with CLL/SLL, including those with genomic high-risk features. CR, uMRD rates, PFS, and OS appear favorable. The safety profile of I+V was consistent with known AEs for each agent; no new safety signals were identified. Clinical trial information: NCT02910583. [Table: see text]

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Brigatinib (BRG) in ALK+ crizotinib (CRZ)-refractory non-small cell lung cancer (NSCLC): Final results of the phase 1/2 and phase 2 (ALTA) trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9071 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9071-9071

Author(s):

Scott N. Gettinger ◽

Rudolf M. Huber ◽

Dong-Wan Kim ◽

Lyudmila Bazhenova ◽

Karin Holmskov Hansen ◽

...

Keyword(s):

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Phase 1 ◽

Objective Response ◽

Progression Free Survival ◽

Phase 2 ◽

Open Label ◽

Long Term Follow Up

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]

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Flavopiridol (Alvocidib) Induces Durable Responses in Relapsed Chronic Lymphocytic Leukemia (CLL) Patients with High-Risk Cytogenetic Abnormalities

Blood ◽

10.1182/blood.v112.11.46.46 ◽

2008 ◽

Vol 112 (11) ◽

pp. 46-46 ◽

Cited By ~ 5

Author(s):

Thomas S. Lin ◽

Nyla A. Heerema ◽

Gerard Lozanski ◽

Beth Fischer ◽

Kristie A. Blum ◽

...

Keyword(s):

High Risk ◽

Response Rate ◽

Phase 1 ◽

Treatment Options ◽

Progression Free Survival ◽

Complete Response ◽

Lymphocytic Leukemia ◽

Purine Analog ◽

Reduced Intensity

Abstract Background: Relapsed CLL patients (pts) with high-risk cytogenetic features have limited treatment options. Flavopiridol induces p53-independent apoptosis of CLL cells in vitro. We previously demonstrated that a pharmacokinetically (PK) derived dosing schedule administering flavopiridol by 30-min IV bolus (IVB) followed by 4-hr continuous IV infusion (CIVI) achieves the necessary serum concentration to induce apoptosis and is clinically active in pts with relapsed, genetically high-risk CLL. Study Design and Treatment: We report response and median progression free survival (PFS) results for 117 pts with relapsed CLL (n=107) or small lymphocytic lymphoma (n=10) treated on successive phase 1–2 studies of this PK-derived schedule. Pts received flavopiridol by 30-min IVB followed by 4-hr CIVI weekly for 4 doses every 6 weeks (n=79), or weekly for 3 doses every 4 weeks with pegfilgrastim support (n=38), for up to 6 cycles. Twenty pts received 30 mg/m2 IVB + 30 mg/m2 CIVI, and 3 pts received 40 mg/ m2 IVB + 40 mg/m2 CIVI. The remaining pts received 30 mg/m2 IVB + 30 mg/m2 CIVI for the first 1 or 5 dose(s) followed by dose escalation to 30 mg/m2 IVB + 50 mg/m2 CIVI beginning with dose 2 or dose 6 if severe tumor lysis was not observed. Pt Characteristics: Eighty pts were male (68%), median age was 60 years (range, 36–84), and 22 pts were age 70 or older (19%). Median number of prior therapies was 4 (range, 1–14); 116 pts had received prior purine analog therapy, and 85 pts (73%) were refractory to (n=82) or intolerant of purine analog (n=3). Ninety-three pts were Rai stage III/IV (79%), and 85 pts had bulky lymph nodes □ 5 cm (73%). Response Assessment: All 117 pts were evaluated for response by NCI 1996 Working Group criteria. Overall response rate (ORR) was 48%, including 52 partial responses (PR), 3 nodular PR (nPR), and 1 complete response (CR). Seven responders were taken to reduced intensity allogeneic stem cell transplants (SCT) and were censored. Median PFS of the 49 other responders was 10 months. Ten pts remain in remission with a median PFS of 12 months (range, 7–22.5). Six responders relapsed and received repeat flavopiridol therapy; 5 pts responded (4 PR, 1 CR) with a median PFS of 12.5 months. Forty-one of 85 pts (48%) with bulky adenopathy; 23 of 53 pts (43%) with a complex karyotype; 20 of 40 pts (50%) with del(17p13), resulting in loss of p53; and 29 of 49 pts (59%) with del(11q22), resulting in loss of the ATM tumor suppressor gene; responded to therapy. Median PFS was 10–12 months in all cytogenetic groups. Conclusions: Flavopiridol achieves durable responses in heavily treated, relapsed CLL pts with bulky adenopathy and poor-risk cytogenetic features. Flavopiridol allows pts who are not SCT candidates to achieve sufficient reduction of their disease to undergo reduced intensity allogeneic SCT. Pts who respond to flavopiridol and subsequently relapse may respond to repeat therapy. Based on these promising results, a phase 2 registration study is ongoing. All Patients Complex del(17p13) del(11q22) N 117 53 40 49 Response rate 48% 43% 50% 59% Median PFS 10.0 months 10.0 months 12.0 months 10.7 months

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ABT-165 plus FOLFIRI versus bevacizumab plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bevacizumab.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.tps720 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. TPS720-TPS720

Author(s):

Zev A. Wainberg ◽

Lan Wang ◽

Huibin Yue ◽

Monica Motwani ◽

Sreeneeranj Kasichayanula ◽

...

Keyword(s):

Tumor Regression ◽

Phase 1 ◽

Performance Status ◽

Objective Response ◽

Laboratory Data ◽

Progression Free Survival ◽

Phase 2 ◽

Open Label ◽

Human Colon Cancer

TPS720 Background: Dual variable domain immunoglobulin ABT-165 targets human vascular endothelial growth factor (VEGF) and delta-like ligand 4 (DLL4). Combined VEGF and DLL4 blockade increased inhibition of subcutaneous xenograft growth of human colon cancer-derived cell lines versus blockade of either axis alone. In vivo, ABT-165 plus chemotherapy (CT) induced tumor regression with improved efficacy, vs anti-VEGF monoclonal antibody plus CT. In a phase 1 study, tolerable recommended phase 2 dose was identified for ABT-165 plus FOLFIRI and showed promising efficacy. This phase 2 trial in progress assesses efficacy/safety of ABT-165 plus FOLFIRI vs bevacizumab (bev) plus FOLFIRI in patients with second-line mCRC. Methods: This is an open-label, multicenter, phase 2 randomized (1:1) trial (NCT03368859) in patients (≥ 18 years; Eastern Cooperative performance status: 0–1) with histologically/cytologically confirmed mCRC who progressed after fluoropyrimidine/oxaliplatin and bev. ABT-165 (2.5 mg/kg) plus FOLFIRI (irinotecan: 180 mg/m2; leucovorin: 400 mg/m2; fluorouracil bolus: 400 mg/m2, infusion: 2400 mg/m2) or bev (5 mg/kg) plus FOLFIRI are given intravenously on day 1 of each 14-day cycle, until disease progression/intolerable toxicity. Primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), objective response rate (ORR), and safety. Exploratory endpoints include biomarkers predictive for efficacy/safety, correlation of DLL4 levels with PFS, OS, and ORR, pharmacodynamic effects, and efficacy/safety-exposure relationships in ABT-165 arm. Hazard ratios of PFS and OS comparing the 2 groups are estimated using Cox proportional hazard model. Kaplan-Meier methodology is used to estimate PFS and OS curves, median PFS and OS, and their 90% confidence intervals. Safety is assessed by ABT-165 exposure, adverse events (AEs), serious AEs, all deaths, and changes in laboratory data and vital signs. Archival tissue is collected and evaluated for DLL4 expression and angiogenesis signature. Approximately 100 patients are planned to be enrolled, with recruitment initiated January 2018. Clinical trial information: NCT03368859.

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