A Research of NVL-655 in Sufferers with Superior NSCLC and Different Strong Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1)
https://clinicaltrials.gov/examine/NCT05384626?time period=NCT05384626&rank=1
Sponsor: Nuvalent, Inc.
Research Director: Viola Zhu, MD, PhD, Nuvalent Inc.
Research Contact: Tina Kehrig, 857-357-7000, clinicaltrials@nuvalent.com
Who is that this trial for: NVL-655 is a 4th era, brain-penetrant, ALK TKI inhibitor created to beat a number of limitations noticed with at the moment obtainable therapies. NVL-655 is designed to have exercise in tumors which have developed resistance to first, second, and third-generation ALK inhibitors, together with tumors with the solvent entrance G1202R mutation or compound mutations G1202R/L1196M (“GRLM”), G1202R/G1269A (“GRGA”), or G1202R/L1198F (“GRLF”). In different phrases, it’s for sufferers for whom different ALK TKIs have failed underneath sure situations. NVL-655 has been optimized for CNS (central nervous system) penetration to enhance remedy choices for sufferers with CNS metastases. ALK-selectivity is emphasised to reduce CNS negative effects associated to off-target inhibition of different related kinases (like NTRK particularly). Unintended effects of different ALK TKIs together with cognitive impairment, temper issues, sleep issues, dizziness, ataxia (poor muscle management), and weight achieve, amongst others, have confirmed to be minimal with NVL-655 in trial outcomes revealed so far. It’s anticipated that NVL-655’s distinctive molecular construction will make it a extra sturdy remedy than prior ALK TKIs.
Scientific Rationale: Following remedy with 1st and/or 2nd era ALK therapies, roughly 40% of sufferers develop the G1202R solvent entrance mutation (as decided by tissue or liquid biopsy), which confers resistance to crizotinib, ceritinib, alectinib, and brigatinib. Third era ALK TKI lorlatinib has been accredited for treating sufferers who’ve beforehand acquired 1st and/or 2nd era ALK therapies. Nevertheless, compound mutations, together with G1202R/L1196M, G1202R/L1198F, and G1202R/G1269A, have been noticed in these sufferers with progressive illness following lorlatinib. Whereas 30-40% of ALK+ NSCLC sufferers have central nervous system (CNS) metastases at analysis, superior sufferers with a historical past of ALK TKI remedies present the next incidence of CNS metastases of about 60%. NVL-655 has been designed to handle these points.
Inclusion Standards: That is the Part 2 portion of the unique Part 1/2, dose escalation and enlargement examine designed to judge the protection and tolerability of NVL-655, decide the really useful section 2 dose (RP2D), and consider the antitumor exercise in sufferers with superior ALK-positive NSCLC and different stable tumors. Remedy consists of a tablet (or drugs) taken orally. Part I started in Could 2022, Part II started in February 2024, and the trial is predicted to be accomplished in March 2026 after enrolling 214 sufferers. An uncommon and patient-friendly inclusion criterion is accepting sufferers age 12 and over (usually sufferers 18 and over are included). There are six cohorts within the Part II trial. Cohort 2a: Sufferers with domestically superior or metastatic NSCLC harboring an ALK rearrangement who’ve acquired 1 prior 2nd-generation ALK TKI (ceritinib, alectinib, or brigatinib). As much as 2 prior traces of chemotherapy and/or immunotherapy are allowed. Cohort 2b: Sufferers with domestically superior or metastatic NSCLC harboring an ALK rearrangement, who’ve acquired 2-3 prior ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib). As much as 2 prior traces of chemotherapy and/or immunotherapy are allowed. Cohort 2c: Sufferers with domestically superior or metastatic NSCLC harboring an ALK rearrangement, who’ve acquired lorlatinib as the one prior ALK TKI remedy. As much as one prior line of chemotherapy and/or immunotherapy acquired previous to lorlatinib is allowed. Cohort second: Sufferers with domestically superior or metastatic NSCLC harboring an ALK rearrangement, who’re naïve to ALK TKI remedy. As much as one prior line of chemotherapy and/or immunotherapy is allowed. Cohort 2e: Sufferers with domestically superior or metastatic NSCLC harboring an ALK rearrangement, not eligible for different Part 2 cohorts. Cohort 2f: Sufferers with different stable tumors harboring an ALK rearrangement or activating ALK mutation, who’ve acquired ≥1 prior systemic anticancer remedy, or for whom no passable commonplace remedy exists.
Exclusion Standards: Sufferers usually are not eligible for the trial if their most cancers has a recognized oncogenic driver alteration apart from ALK, if they’ve a recognized allergy/hypersensitivity to any inactive pharmaceutical elements of NVL-655, if they’ve had main surgical procedure inside 4 weeks of the examine entry, in the event that they produce other anticancer remedy ongoing, or if they’re actively receiving systemic remedy or direct medical intervention on one other therapeutic medical examine.
Availability: As of September 21, 2024, 229 sufferers have been enrolled within the Part II portion of this trial, with an anticipated complete enrollment of 470. On the time of this writing the trial is open at fifty-four places in america, Australia, Canada, France, Italy, Korea, Netherlands, Singapore, Spain, Taiwan, and the UK. Contact info might be discovered right here: https://clinicaltrials.gov/examine/NCT05384626?time period=NCT05384626&rank=1#contacts-and-locations
Some Particulars: Nuvalent, Inc. is a medical stage biopharmaceutical firm targeted on creating exactly focused therapies for sufferers with most cancers. It’s a publicly traded firm that was based in 2017, is listed on the NASDAQ change underneath ticker image NUVL, and is headquartered in Cambridge, Massachusetts. On August 2, 2021, the Firm accomplished an preliminary public providing (IPO) at $17/share. At this writing the inventory worth is $90.70/share. As of June 30, 2024, the corporate reported money, money equivalents, and marketable securities of roughly $658.0M, and had a web lack of $101.6M for the six months ended June 30, 2024. A public providing in September 2024 raised a further $575M of gross proceeds. Different investigational medicine in section II and Part I trials are for ROS1 and HER2 constructive NSCLC respectively. Scientific advisors to Nuvalent embody a number of key opinion leaders (KOLs) within the ALK discipline which are well-known throughout the ALK NSCLC neighborhood. Amongst these are Dr. Ross Camidge (MD, PhD, Director of Thoracic Oncology and Joyce Zeff Chair in Lung Most cancers Analysis at College of Colorado Most cancers Centre, Denver), Dr. Aaron Hata (MD, PhD, Translational Analysis Advisor at Harvard Medical College, Mass Common Most cancers Heart), and Dr. Pasi Jänne (MD, PhD, Medical Advisor at Harvard Medical College, Dana Farber Most cancers Institute). www.nuvalent.com
ALKOVE-1 Part 1 Replace at ESMO 2024: From June 2022 to February 2024, the Part 1 portion of ALKOVE-1 enrolled 133 sufferers (131 NSCLC, 2 different stable tumors). Sufferers acquired NVL-655 orally at dose ranges starting from 15 to 200 mg each day, and 150 mg each day was chosen because the really useful section 2 dose (RP2D). The affected person inhabitants was closely pre-treated, with a median of three prior traces of remedy (vary 1 – 9). 46% (61/133) of sufferers had ≥3 prior ALK TKIs, and 56% (74/133) had prior chemotherapy. Notably, 84% (111/133) of sufferers acquired prior lorlatinib and 51% (68/133) had any secondary ALK resistance mutation together with 26% (34/133) with compound (≥2) ALK mutations, highlighting the differentiated nature of this inhabitants from prior trials of investigational ALK inhibitors. 56% (75/133) had historical past of CNS metastases, together with instances of illness development following remedy with the brain-penetrant TKI lorlatinib. As of the deadline of June 15, 2024, 103 closely pre-treated sufferers with ALK-positive NSCLC handled throughout all doses had been response-evaluable, of whom 39 had been handled on the RP2D. The median follow-up for the all-treated inhabitants was 8.0 months (vary 0.2, 22.5). Remedy with NVL-655 resulted in sturdy medical responses (ORR by RECIST 1.1) throughout key subgroups of response-evaluable sufferers handled on the RP2D and throughout all dose ranges.
See response knowledge right here: https://traders.nuvalent.com/2024-09-14-Nuvalent-Highlights-Presentation-of-Medical-Information-at-ESMO-2024-for-Parallel-Lead-Packages-for-ROS1-and-ALK-positive-NSCLC-and-Accelerated-Improvement-Timelines
Jeffrey M. Sturm, BS, MA, MBA
ALK Optimistic www.alkpositive.org
Member, Analysis Acceleration Committee
Member, Medical Trials Committee
Member, Board of Administrators
9-year ALK NSCLC survivor