SWOG 0204; Phase 2 Trial of Thalidomide (T) + Dexamethasone (D) Induction Followed by Tandem Autotransplant (TAT) and Prednisone (P) + T Maintenance for Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1169-1169 ◽  
Author(s):  
Mohamad A. Hussein ◽  
Jason McCoy ◽  
Andrzej Jakubowiak ◽  
Brian G. Durie ◽  
John J. Crowley ◽  
...  
Keyword(s):  
Bone Pain ◽  
Phase 1 ◽  
Induction Phase ◽  
Phase Ii Trials ◽  
Gm Csf ◽  
Phase 2 Trial ◽  
Unknown Reason ◽  
Biologic Effect ◽  
Timely Fashion ◽  
Grade 3

Abstract Background: TAT has recently been shown to double the 7-yr event-free (EFS) & overall survival (OS) rates achieved with a single AT (20% & 40%; IFM94). Completion of TAT in most randomized & phase II trials seldom exceeds 70%, due to toxicities encountered with prolonged induction chemotherapy & posed by the 1st AT. TD is effective salvage therapy &, when used up-front, effects high response rates including ~15% CR. To reduce induction toxicities & thus deliver TAT in a timely fashion to the majority of pts, SWOG embarked on a trial of TD induction, modest-dose cyclophosphamide (CTX) for PBSC mobilization, melphalan (MEL)-based TAT & subsequent PT maintenance. Methods: Between 6/15/02 &, as of 7/29/05, 130 eligible & analyzable newly diagnosed pts with active MM have been enrolled. T was administered at a daily dose of 100mg & incremented by 50mg a week to a dose not to exceed 400mg; the start dose of the T was later reduced to 50mg. D was given at 40mg a day on days 1–4, 9–12 & 17–20 & repeated on day 35. Following 3 TD cycles, CTX was administered at 1g/sqm with G-CSF\GM-CSF with an intended minimum PBSC yield of >= 10 x 106 CD34 cells/kg. TAT applied a modest MEL dose of 140mg/sqm for the 1st AT & the standard MEL 200mg/sqm dose with the 2nd AT. Maintenance therapy was with P 50mg on alternating days & daily T 200mg with dose reduction as needed for toxicities. Results: 28 SWOG institutions have enrolled 130 pts; 77 pts have completed the scheduled 3 TD cycles & PBSC collection (median, 8.2 x 106; range, 1.1 x 106 to 21.0 x 106). 18 pts did not proceed past the induction phase: 4 progressed; 3 came off study due to toxicity, 4 due to insurance denial, 6 because of pt preference; & one pt died. 25 pts achieved a response rate (CR+R+PR) of 80% during the induction phase; 1 achieved CR & 19 R/PR. Of 77 pts registered to the transplant step, 35 are currently receiving AT1 & candidates for AT2. Of 27 pts completing AT2, the median time to AT2 was 7.9 months from initial registration & 2.1 months from AT1. 9 pts received AT1 & will not proceed to AT2 because of inadequate collection (6 pts), or unknown reason (3 pts). Toxicity data are available for 102 pts completing induction & mobilization: Grade 3 toxicities were reported for GI (9), fatigue (12), bone pain (7) & hypercoagulability (4); grade 4 toxicity pertaining to hypercoagulable state was noted in 5 pts & bone pain in 2 pts. With an incidence of deep venous thrombosis (DVT) of 21% in the first 23 patients enrolled, the protocol was amended to decrease the start dose of thalidomide to 50mg from 100mg, with a 50mg weekly increment; the current incidence of DVT is less than 10%. No unanticipated toxicities have occurred during the second transplant. Conclusion: Our preliminary data suggest that TD for induction starting at 50mg of thalidomide & incrementing by 50mg weekly to a target dose of 400mg is well tolerated & allows for all pts to receive AT2 in a timely fashion (2.1 months from AT1) with no increase in toxicity. Larger numbers & longer follow up should clarify if the superior results associated with the timeliness of the AT2 are secondary to a biologic effect or a selection bias.

A phase I combination study of vigil and atezolizumab in recurrent/refractory advanced-stage ovarian cancer: Efficacy assessment in BRCA1/2-wt patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3002-3002
Author(s):  
Rodney Paul Rocconi ◽  
Erin E. Stevens ◽  
Justin N. Bottsford-Miller ◽  
Sharad A. Ghamande ◽  
Phylicia Aaron ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Activation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Autologous Tumor ◽  
Advanced Stage ◽  
Gm Csf ◽  
Study Results ◽  
Grade 3 ◽  
Overall Survival Benefit

3002 Background: Recent studies have shown poor clinical outcomes and limited survival advantage to checkpoint inhibitors (CIs) in advanced stage ovarian cancer (OvC). Vigil is a personalized precision vaccine constructed from autologous tumor tissue transfected with a DNA plasmid encoding GM-CSF and bi-shRNA-furin thereby creating TGFβ expression control and enhancing immune activation. Phase 1 and 2 trials in OvC demonstrate safety, functional immune activation and clinical response benefit. Combining Vigil with CIs may broaden responsiveness of immunotherapy in OvC. Methods: This is a randomized, 3-part safety Phase 1 study of Vigil in combination with Atezolizumab in recurrent OvC patients. Part 2 is a randomized, intra-patient crossover study of Vigil first (VF) or Atezolizumab first (AF) for two cycles followed by sequence of the combination of the two agents. Vigil (1 x 106 or 1 x 107 cells/ml) or Atezolizumab (1200mg) were administered 1x every 21 days each cycle until progression or untoward adverse event. We now report the preliminary results of part 2 of the study. Results: Twenty-one patients were randomized (1:1) to VF (n = 11) or AF (n = 10), groups were similar in demographics. Grade 3/4 toxic events occurred in 17% of AF patients compared to 3% in VF patients. Median OS of VF patients (n = 11) was not reached vs. AF (n = 10) 10.8 months suggested modest advantage to VF (HR 0.33, one-sided p 0.097). However, the subset analysis of BRCA1/2 wild type (wt) demonstrated more significant overall survival benefit in VF (n = 7) median OS not reached vs. AF (n = 7) 5.2 months (HR 0.12, one-sided p 0.015). Conclusions: The combination of Vigil immunotherapy and checkpoint inhibitor atezolizumab in recurrent OvC demonstrated safety and suggest a lower toxicity profile and a significant OS advantage in recurrent BRCA1/2-wt OvC patients treated with Vigil first followed by the combination of Vigil and Atezolizumab. Clinical trial information: NCT03073525 . [Table: see text]

QOLP-04. THE KETOGENIC DIET PLUS STANDARD CARE FOR RECENTLY DIAGNOSED GLIOBLASTOMA: A PHASE 1 SAFETY AND FEASIBILITY TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi183-vi183
Author(s):  
Jethro Hu ◽  
L J Amaral ◽  
Gillian Gresham ◽  
Thomas Nelson ◽  
Amelia Welborn ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Phase 1 ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Primary Objective ◽  
Feasibility Trial ◽  
Phase 2 Trial ◽  
Related Quality ◽  
Health Related ◽  
Grade 3

Abstract INTRODUCTION There is abundant interest in the potential therapeutic and supportive role of a ketogenic diet (KD) for glioblastoma patients. We conducted a single-arm phase 1 trial to assess the safety and feasibility of KD plus standard-of-care (SOC) in glioblastoma patients (NCT03451799). METHODS Adults within 3 months of diagnosis participated in a 16-week intervention of a classic 3:1 KD (grams fat : grams carbohydrate + protein) with dietitian support. Blood glucose and ketone levels were assessed twice daily (Keto-Mojo), with remote monitoring of daily weight and activity (Fitbit). The primary objective was to assess safety (weight stability, CTCAE) and feasibility (maintaining ketosis > 0.3mM for > 50% of study period). Secondary objectives included assessments of progression-free survival (PFS), overall survival (OS), health-related quality of life (HRQOL), and cognition (MoCA). RESULTS From 04/2018-02/2021, 14 patients were evaluable: female:male, 8:6, median age 55 years, KPS 80, BMI 24.5. MGMT promoter methylation: 6 present, 7 absent, 1 indeterminate. Adherence to KD was high, with all patients maintaining ketosis ( > 0.3mM) > 50% and 11 patients maintaining ketosis > 85% of study days. Adverse events (> Grade 2) potentially attributable to KD: appetite loss (Grade 2: 2); fatigue (Grade 2: 5); flu-like symptoms (Grade 2: 1); constipation (Grade 2: 5, Grade 3: 1). No patients were removed from study for safety reasons. HRQOL was stable, with improvements in role function (not statistically significant). MoCA score improved in 10/14 patients. Median PFS and OS from KD initiation were 11.7 and 29.1 months, respectively. CONCLUSION Our findings suggest that a supervised KD plus SOC is safe and feasible in glioblastoma patients. KD was well-tolerated with encouraging trends in HRQOL and cognition. PFS and OS in this small trial compare favorably to historical control. A multicenter phase 2 trial powered to assess efficacy is planned.

Phase 2 trial of 177Lutetium (177Lu) radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody (mAb) J591 (177Lu-J591) in patients (pts) with metastatic androgen-independent prostate cancer (AIPC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4613-4613 ◽  
Author(s):  
M. J. Morris ◽  
M. I. Milowsky ◽  
N. Pandit-Taskar ◽  
C. Divgi ◽  
K. A. David ◽  
...  
Keyword(s):  
Median Time ◽  
Primary Endpoint ◽  
Phase 1 ◽  
Imaging Study ◽  
Hematologic Toxicity ◽  
Disease Response ◽  
Phase 2 Trial ◽  
Measurable Disease ◽  
Grade 3 ◽  
Metastatic Sites

4613 Background: J591 is an anti-PSMA mAb targeting the extracellular domain of PSMA, a highly PC restricted glycoprotein. 177Lu linked to J591 via a DOTA chelate was evaluated in a phase 1 trial in pts with metastatic AIPC demonstrating acceptable toxicity (MTD = 70 mCi/m2), excellent targeting of metastatic sites and biologic activity. Methods: Pts with progressive metastatic AIPC receive a single dose of 177Lu -J591 in two cohorts (65 and 70 mCi/m2). Cohort 1: 15 pts; Cohort 2: 17 pts. The primary endpoint is PSA and measurable disease response assessed at wk 12. Secondary endpoint is to evaluate toxicity. One 177Lu imaging study is done at 1 week post-treatment to confirm tumor targeting. Results: 14 pts, median age 73 (5 chemo-naïve), have been treated on this ongoing 2-center study. One pt with bone-only metastases achieved an 87% decline in PSA by day 85 with resolution of bone pain. Bone scan at wk 12 revealed a flare response. As of day 222, the pt has not required additional therapy. PSA stabilization (< 25% PSA rise above baseline) has been seen in 4 pts lasting 16 wks in 2 pts, 18 wks (1 pt) and 23 wks (1 pt), respectively. One pt withdrew at wk 56 without PSA progression. Of 5 pts with measurable disease, no objective responses were seen. Grade 3 and 4 thrombocytopenia occurred in 6 and 4 pts, respectively. 12/14 pts recovered plt counts to ≥ 150 x 109/L (median time to recovery = 22 d). Grade 3 and 4 neutropenia occurred in 7 and 1 pts, respectively. 13/14 pts had ANC recovery to ≥ 2 x 109/L (median time to recovery = 13 d). No significant drug-related non-hematologic toxicity has occurred. Excellent targeting of known sites of PC metastases has been observed in all pts. Conclusions: 177Lu-J591 demonstrates anti-tumor activity in pts with AIPC with one pt achieving the primary endpoint (≥ 50% PSA decline) and 4 pts with PSA stabilization at a dose of 65 mCi/m2. Support: NIH CA102544 , NCRR M01RR00047, DOD PC031175 , David H. Koch Foundation, Cancer Research Institute, MSKCC Experimental Therapeutics Ctr, McCoey Fund, BZL Biologics, Inc. and Millennium Pharmaceuticals, Inc. No significant financial relationships to disclose.

A phase 1 study of weekly, divided dose perifosine in patients (pts) with non-small cell lung cancer (NSCLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13063-13063 ◽  
Author(s):  
I. C. Henderson ◽  
D. R. Spigel ◽  
J. J. Nemunaitis ◽  
D. A. Richards ◽  
J. E. Liebmann ◽  
...  
Keyword(s):  
Phase 1 ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Weekly Schedule ◽  
Ecog Performance Status ◽  
Phase 2 Trial ◽  
Starting Dose ◽  
Grade 3 ◽  
Nsclc Patients

13063 Background: Perifosine (P) is known to modulate signal transduction pathways, including Akt which is frequently constitutively activated in NSCLC. The half life of P is ∼100 hours and GI toxicities are dose limiting. Studies of a single dose weekly regimen found that the maximum tolerated dose (MTD) was 800 mg. This study was undertaken to see if a higher MTD could be reached using divided doses in NSCLC patients. Methods: Twenty NSCLC patients (pts) were given P, 300 mg, at intervals of 4–6 hours with no more than 4 doses in a 24 hour period. The starting dose was 900 mg and this was escalated by 300 mg/week in subsequent pts to an MTD of 1800 mg. Results: The median age of pts was 62 (range 39–79); 9 were male and median ECOG performance status was 1 (range 0–1). Nineteen pts had received prior chemotherapy (median 2 regimens) and 18 prior radiotherapy. Three pts were entered at each dose and the cohort expanded to 6 pts if 1 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during the first week of therapy. A dose level was toxic if 2 or more pts experienced a DLT. The median time on study was 8 weeks (range 2–28). Seventy-seven percent of pts had no dose reduction (85% of those on 900 mg, 95% on 1200, 72% on 1500, and 78% on 1800 mg). In cohort 1, one pt died within a week without toxicity from P and 1 pt experienced grade 3 nausea, so this cohort was expanded. The other pts in the cohort had no toxicity. In cohort 4 one pt. took 300 mg daily for 6 days and was considered inevaluable. In cohort 3, grade 3/4 toxicity was not observed until after day 28 in 3 pts. Fifteen pts were evaluable for response; 1 had an unconfirmed partial response and 2 had stable disease. Conclusions: This study demonstrated that higher doses of P can be administered on a weekly schedule with divided doses. Weekly doses of 900 and 1200 mg lead to almost no toxicity in most pts. This study has been expanded to a phase 2 trial with direct comparison of weekly and daily doses. The grade 3/4 toxicities for each cohort are given in the table below. [Table: see text] [Table: see text]

Perifosine (P), active as a single agent for renal cell carcinoma (RCC), now in phase I trials combined with tyrosine kinase inhibitors (TKI)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15622-15622 ◽  
Author(s):  
J. Stephenson ◽  
M. Schreeder ◽  
J. Waples ◽  
J. Hargis ◽  
L. Campos ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Two Phase ◽  
Phase 1 Trials ◽  
Phase 2 Trial ◽  
Hand Foot Syndrome ◽  
Grade 3

15622 Background: P is an oral alkylphosphocholine with effects on multiple pathways including Akt, MAPK and JNK. Akt/S6 is often activated in RCC and associated with resistance. In a phase I study of P, 3/6 RCC patients (pts) had stable disease (SD) lasting for 4, 6 and 14 months (m). RCC was further assessed in a broad phase 2 trial, and subsequently, two phase 1 trials combining P with TKIs have been initiated. This is an update of the phase II and first report of the phase I combination trials. Methods: From 3/05 to 5/06 241 pts, including 13 with RCC, were randomized to P, 50 mg daily or 1200 mg weekly. Subsequently the protocol was amended to P, 100 mg daily or 900 mg weekly, and enrollment continues. Pts with measurable disease who received at least 2 courses of P and at least one tumor measurement after initiation of P were considered evaluable for response using RECIST criteria. After demonstrating P activity in RCC, two phase 1 studies of P combined with either sorafenib (SOR) or sunitinib (SUT) were initiated. In each study, the dose of P is escalated from 50 mg qd to 50 mg tid. SOR is escalated from 400 mg qd to 400 mg bid and SUT from 25 to 50 mg qd for 4 weeks out of 6. Results: In the broad phase II study, 6 pts (66%) achieved clinical benefit. (See table ) including 3 pts (33%) with partial responses [duration 4, 6.5 and 9 m] and 3 pts (33%) with SD [9+, 9+ and 10 m]. Three pts progressed. The main toxicities were grade 1 nausea, vomiting, diarrhea, and fatigue. Daily P was significantly better tolerated than weekly and data are presented in detail in another abstract. Enrollment in cohorts 1 and 2 of the P/SOR study is complete. No grade 3 or 4 toxicities and increase in hand foot syndrome has been seen. Accrual to cohort 1 of the P/SUT study is also complete. Enrollment will be complete by May 2007. Conclusions: P is active in RCC. Phase 1 trials of P with TKIs have demonstrated no increased toxicity with less than maximal doses of P and TKI [Table: see text] No significant financial relationships to disclose.

A phase II trial of radiation and cetuximab followed by irinotecan/cetuximab for children with newly diagnosed diffuse pontine tumors and high-grade astrocytomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10030-10030 ◽  
Author(s):  
Margaret Macy ◽  
Mark W. Kieran ◽  
Susan N. Chi ◽  
Kenneth J. Cohen ◽  
Tobey MacDonald ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase 1 ◽  
Progression Free Survival ◽  
External Beam Radiation ◽  
High Grade ◽  
Newly Diagnosed ◽  
Beam Radiation ◽  
Phase 2 Trial ◽  
Correlative Studies ◽  
Grade 3

10030 Background: Diffuse intrinsic pontine gliomas (DIPG) and high-grade astrocytomas (HGA) have dismal prognoses. We previously demonstrated in a phase 1 study that cetuximab and irinotecan was a safe and tolerable regimen. Consequently, we initiated this 2-strata phase 2 trial to investigate the safety and efficacy of weekly cetuximab given with involved field external beam radiation therapy followed by 10 cycles of cetuximab and irinotecan for DIPG and HGA as determined by the 1-year progression-free survival. Methods: Eligible patients aged 3-21 years with newly diagnosed HGA or DIPG were enrolled to parallel strata. All patients received radiation therapy (5940 cGy) with concurrent cetuximab at 250mg/m2 IV weekly for 6 weeks. Following radiation, patients received cetuximab (250mg/m2 IV) weekly and irinotecan (16mg/m2/day IV) daily x 5 for two weeks every 21 days for 30 weeks. Tumor, serum, and CSF samples were collected for correlative studies. Sera collected at the onset of rash were analyzed for inflammatory and immune-related cytokines. Results: Forty-eight patients (27 DIPG, 21 HGA) were enrolled and 45 were treated (median age 8 years; range: 3–19). Toxicities were manageable; the most common adverse events were fatigue, gastrointestinal complaints, neutropenia, rash, headache, electrolyte abnormalities, elevated ALT/AST, and fever. Grade 3-4 events in ≥10% of patients were hypokalemia and lymphopenia. 4 patients experienced cetuximab-related hypersensitivity reactions (2 grade 3 reactions). The median PFS was 9.5 months (95% CI: 7.0-12.2) for HGA and 7.8 months (7.0-8.6) for DIPG with a 1-year PFS±SE of 24±10% and 25%±10% respectively. The median OS for HGA was 17.7 months (95% CI: 14.1-18.0) and 11.5 months (8.8-14.2) for DIPG. Biological correlative studies will be presented. Conclusions: Cetuximab and radiation therapy followed by cetuximab and irinotecan is well tolerated in children. Based on the 1-year PFS, this regimen may deserve further investigation in patients with DIPG. Biological correlative studies will delineate the mechanisms of the rash and possible implications for EGFR-targeted therapeutics in such patients. Clinical trial information: NCT01012609.

scholarly journals Bortezomib (Velcade), Thalidomide, Dexamethasone and Panobinostat (VTD-P) Is a Safe, Well Tolerated and Efficacious Regimen for Patients with Relapsed Multiple Myeloma: Preliminary Results of the Muk-Six Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1826-1826 ◽  
Author(s):  
Rakesh Popat ◽  
Sarah R Brown ◽  
Louise M Flanagan ◽  
Andrew Hall ◽  
Bhuvan Kishore ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Response Rate ◽  
Phase 1 ◽  
Dose Finding ◽  
Thrombosis Prophylaxis ◽  
Induction Phase ◽  
Advisory Committees ◽  
Serious Adverse Events ◽  
Grade 3

Abstract Introduction: VTD is an effective regimen for patients with multiple myeloma and forms a backbone for the addition of novel agents. The MUK-six trial aimed to improve the efficacy by adding Panobinostat, a now FDA approved pan-histone deacetylase inhibitor that demonstrated synergy with proteasome inhibition and immunomodulatory agents in pre-clinical models. We have previously reported the phase 1 dose finding part which determined the MTD of panobinostat with VTD to be 20mg. Here we present the efficacy results from the recommended dose (RD) expansion phase (primary end point) and safety, tolerability data for all patients during the induction phase of the study. Methods: MUK-six was a multi-centre UK Phase I/IIa trial for patients with relapsed and relapsed/ refractory myeloma who had received between 1 and 4 prior lines of therapy. Subjects received VTD-P (bortezomib 1.3mg/2sc days 1 and 8, thalidomide 100mg daily (50mg if pre-existing neuropathy), dexamethasone 20mg days 1, 2, 8, 9 and panobinostat 20mg days 1, 3, 5, 8, 10, 12) every 3 weeks for up to 16 cycles (induction) followed by 1 year of panobinostat maintenance. Those planned for autologous stem cell transplantation (ASCT) received a minimum of 6 cycles of VTD-P. All patients treated with VTD-P received venous thrombosis prophylaxis as per institutional practice. Responses were assessed using modified IWG uniform response criteria and toxicity graded by CTCAE V4.0. Results: 46 patients were treated at the RD and were of a median age of 60 years (41-76). 80.4% had received one prior line of therapy (range 1-4), 71.7% had prior bortezomib and 39.2% prior thalidomide. Most patients were ISS 1 (60.9%), 45.7% had adverse FISH lesions at baseline, 8.7% had 17p deletion. 6 patients remain on treatment at the time of this abstract. 51.3% of patients came off study to proceed to ASCT. The overall response rate (≥PR) for patients receiving at least one dose of panobinostat was 91.3%, ≥VGPR 45.7% (CR 6.5%, VGPR 39.1%, PR 45.7%). The ≥VGPR rate for those with standard FISH was 52.1% vs 42.9% for adverse FISH. Those treated at first relapse had higher overall responses to those treated later in their disease course (≥PR 94.6% vs 77.8%). Responses were independent of prior bortezomib exposure (≥PR 90.9%, ≥VGPR 45.5% vs PR≥92.3%, ≥VGPR 46.2%). Treatment was generally well tolerated, with a mean panobinostat dose of 17.4mg (86.8% of the RD) delivered across all cycles. 32.1% of those starting at 50mg thalidomide stopped the drug due to toxicity, and 52.6% of those starting at 100mg required dose reductions/stopping. 46 serious adverse events were reported in 27 patients which were mainly infections (17/46, 37.0%). The commonest grade 3-4 toxicities reported for all 57 patients were: neutropenia (14, 24.6%), hypophosphatemia (11, 19.3%), thrombocytopenia (8, 14.1%) and diarrhoea (6, 10.5%). Of note there were no reports of ≥ grade 3 neuropathy. The most frequent grade 1-2 toxicities were fatigue (50, 87.7%), neuropathy (43, 75.5%), constipation (35, 61.4%), diarrhoea (35, 61.4%), bone pain (33, 57.9%), and nausea (27, 47.4%). 2 patients withdrew consent due to toxicity. Conclusions: This study demonstrated that panobinostat can be safely given in combination with VTD and appears highly effective with a response rate of 91.3%, ≥VGPR 45.6% despite 72% having previous bortezomib. This regimen was well tolerated, in particular the incidence of diarrhoea, neuropathy and asthenia/fatigue appeared lower than that observed in the PANORAMA 2 trial (San Miguel et al., 2014). It is possible that the incorporation of a low intensity subcutaneous bortezomib schedule (2 doses every 3 weeks) contributed to the lesser toxicity. Acknowledgments: This trial was part of the Myeloma UK Clinical Trial Network, ISRCTN: 59395590. Disclosures Popat: Janssen: Honoraria. Off Label Use: Panobinostat: use outside of FDA licence, not yet EU approved. Kishore:Celgene: Other: Conference Sponsorship; Jazz pharma: Other: Conference Sponsorship. Oakervee:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Yong:Janssen: Honoraria; Autolous: Consultancy; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Novartis: Consultancy. Cook:Sanofi: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cavenagh:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Preliminary Results of a Phase 1/2, Multi-Center, Open-Label Study (CLL- 001) Investigating a Stepwise Dose-Escalation Schedule of Lenalidomide in Relapsed or Refractory Chronic Lymphocytic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2104-2104 ◽  
Author(s):  
Clemens M Wendtner ◽  
Daruka Mahadevan ◽  
Stephan Stilgenbauer ◽  
Olga Frankfurt ◽  
Adrian Bloor ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Safety Data ◽  
Lymphocytic Leukemia ◽  
Phase Ii Trials ◽  
Grade 3

Abstract Lenalidomide is an immunomodulatory drug that has demonstrated therapeutic activity in 2 independent phase II trials in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Based on those data a new phase II trial (CC-5013-CLL-001) was designed to compare 25 mg versus 10 mg, the doses used in those completed phase 2 studies. Patients were randomized in the initial protocol design to treatment with either 25 mg of lenalidomide daily for 21 out of each 28-day cycle, or with 10 mg of lenalidomide daily for 28 out of each 28–day cycle. However, when 5 out of 18 patients enrolled developed tumor lysis syndrome (TLS) resulting in 2 fatalities the protocol was amended to a phase I/II trial to determine a safe dose and schedule (Moutouh-de Parseval et al. J Clin Oncol2007, 25: 5047). In this ongoing phase I dose escalation study the safety of several lenalidomide doses was investigated. Patients with prior treatment with an alkylating agent and who have failed fludarabine were started on 2.5 mg of lenalidomide daily, followed by slow intra-patient dose escalation to 5 mg after 28 days. Doses were then escalated as tolerated by 5 mg every 28 days by initial cohort of 6 patients, until the maximum tolerated dose escalation level (MTDEL) was defined or a maximum dose of 25 mg daily. Patients were treated until disease progression, and all patients received TLS prophylaxis with hydration starting 3 days prior to lenalidomide treatment and continuing for at least the first 3 cycles. Seventeen patients, with a median age of 66 years (range 50–76), have been enrolled on the amended protocol. Patients had a median of 4 prior therapies (range 2–14), 56.3% of patients were refractory to fludarabine and 31.3% had prior alemtuzumab therapy. Among these, 77% of patients had bulky lymphadenopathy. Treatment is continued in 13 patients, while 4 patients have discontinued treatment (2 lack of therapeutic effect, 1 grade 4 thrombocytopenia at 2.5 mg every other day in a patient with preexisting thrombocytopenia, and 1 withdrew consent). During therapy, common toxicities included ≥ grade 3 neutropenia [4/17 (23.5%) at 2.5 mg; 3/7 (42.9%) at 5 mg; 2/3 (66.7%) at 10 mg], ≥ grade 3 thrombocytopenia [2/17 (11.8%) at 2.5 mg daily], and tumor flare reaction [TFR; 4/17 (23.5%) at 2.5 mg; 1/7 (14.3%) at 5 mg]. TFR ≥ grade 3 occurred in 2 patients, in one patient at the 2.5 mg dose and in one at the 5 mg dose which was effectively managed with non-steroidal anti-inflammatory drugs, corticosteroids and/or temporary interruption of treatment. On the amended protocol, TLS has not been observed in any patient except 1 in whom laboratory findings consistent with TLS was observed at the 2.5 mg dose. The patient was able to continue treatment without TLS recurrence. To date, the MTDEL has not been reached. At the time of data collection patients were not yet evaluable for clinical response. Preliminary data presented here demonstrate the safety of lenalidomide therapy administered by a step-wise dose escalation with an initial 2.5 mg starting dose in patients with heavily treated CLL. We further observe that use of prophylaxis, as well as frequent monitoring of patients, was effective in decreasing the incidence of TLS. Further data are needed to confirm the optimal dose for lenalidomide in the treatment of CLL. Additional safety data observed in the patients treated on this study will be presented at the meeting.

Safety profile of avelumab in patients with advanced solid tumors: A JAVELIN pooled analysis of phase 1 and 2 data.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3059-3059 ◽  
Author(s):  
Karen Kelly ◽  
Jeffrey R. Infante ◽  
Matthew H. Taylor ◽  
Manish R. Patel ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Safety Profile ◽  
Phase 1 ◽  
Safety Data ◽  
Pooled Analysis ◽  
Clinical Activity ◽  
Thyroid Disorder ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Grade 3

3059 Background: Avelumab is a fully human IgG1 anti–PD-L1 antibody with clinical activity in several tumor types. Pooled safety data from a large phase 1 trial in various tumors and a phase 2 trial in Merkel cell carcinoma (NCT01772004, NCT02155647) were analyzed to further characterize the safety profile of avelumab. Methods: Patients (pts) received avelumab 10 mg/kg 1-hour IV Q2W until progression, unacceptable toxicity, or withdrawal. Treatment-related adverse events (TRAEs) were graded by NCI CTCAE. In post hoc analyses, immune-related adverse events (irAEs) were identified via an expanded AE list and medical review, and infusion-related reaction (IRR) events were identified based on prespecified MedDRA terms, occurring within 1 day or related symptoms that resolved within 2 days of infusion. Results: In 1,738 pts analyzed (phase 1, n = 1,650; phase 2, n = 88) who received ≥1 dose of avelumab for a median of 12 weeks (range 2-138), the most common any grade TRAEs were fatigue (n = 307, 18%), IRR (n = 295, 17%), and nausea (n = 150, 9%). 177 pts (10%) had a grade ≥3 TRAE; most common were fatigue and elevated lipase (17 [1%] each). TRAEs led to discontinuation in 107 pts (6%). Four pts (0.2%) died due to a TRAE. Any grade irAEs occurred in 247 pts (14%), which were grade ≥3 in 39 pts (2%) and considered serious in 43 pts (2%). The most common any grade irAEs were thyroid disorder (n = 98, 6%) and rash (n = 90, 5%). Other irAEs (eg, colitis, hepatitis, pneumonitis, adrenal insufficiency, myositis) each occurred in < 2%. irAEs led to discontinuation in 34 pts (2%). IRR or related symptoms (eg, chills, pyrexia, hypersensitivity) occurred in 439 pts (25%), which were grade 3 in 9 pts (0.5%) and grade 4 in 3 pts (0.2%). An IRR occurred at first infusion in 79% and within first 4 doses in 99%; 63/439 pts (14%) had IRR recurrence in later cycles. IRR led to dose interruption in 152 (9%), infusion rate reduction in 124 (7%), and discontinuation in 35 pts (2%). Conclusions: This large pooled analysis confirms that avelumab has an acceptable safety profile. A minority of pts experienced a grade ≥3 TRAE or irAE and discontinuation due to TRAEs was uncommon. IRRs mostly occurred at first infusion and the rate of recurrence was low. Clinical trial information: NCT01772004, NCT02155647.

Brigatinib (BRG) in crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): Updates from ALTA, a pivotal randomized phase 2 trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20503-e20503 ◽  
Author(s):  
Myung-Ju Ahn ◽  
D. Ross Camidge ◽  
Marcello Tiseo ◽  
Karen L. Reckamp ◽  
Karin Holmskov Hansen ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Phase 1 ◽  
Objective Response ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Best Response ◽  
Grade 3 ◽  
Nsclc Patients ◽  
To Receive ◽  
Randomized Phase 2

e20503 Background: Most ALK+ NSCLC patients (pts) receiving CRZ eventually experience disease progression. Based on promising activity in a phase 1/2 trial, a randomized phase 2 trial of the ALK inhibitor BRG in pts with CRZ-refractory, advanced ALK+ NSCLC (ALTA; NCT02094573) was initiated. Responses and adverse events (AEs) varied with starting dose; therefore, ALTA was designed to evaluate 2 distinct BRG regimens. Methods: Pts were stratified by presence of baseline (BL) brain metastases and best response to prior CRZ and randomized 1:1 to receive BRG at 90 mg qd (arm A) or 180 mg qd with a 7-d lead-in at 90 mg (arm B). Primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Results: In 222 pts (arm A/B, n=112/n=110), median age was 51/57 y; 71%/67% had brain metastases. As of May 31, 2016, 51%/56% (A/B) continued to receive BRG; median follow-up was 10.2/11.0 mo. Table shows efficacy. In pts with measurable BL brain metastases (A/B, n=26/n=18), confirmed intracranial ORR was 46%/67%. Most common treatment-emergent AEs (A/B) were: nausea 36%/43%, diarrhea 21%/39%, cough 23%/36%, headache 28%/30%, vomiting 28%/26%; grade ≥3 AEs included increased CPK 3%/10%, hypertension 6%/6%, pneumonia 3%/5%, increased lipase 5%/3%. A subset of pulmonary AEs with early onset (median: Day 2) occurred in 14/219 (6%) treated pts (3%, grade ≥3); 7/14 pts were successfully retreated. Dose reductions (8%/23%, A/B) and discontinuations (3%/10%) due to AEs were reported. Conclusions: BRG showed substantial activity, robust PFS, and acceptable safety at both dose levels, with numerically improved efficacy (particularly PFS and intracranial ORR) at 180 mg (with lead-in). Clinical trial information: NCT02094573. [Table: see text]

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