Neoplasms

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Skin and Connective Tissue Diseases

Rare Diseases

Gastrointestinal Stromal Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Palbociclib

Sunitinib

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib.

PD-0332991 is formulated as gelatin capsules of 100 mg and 25 mg respectively.

PD-0332991 was administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively.

PD-0332991 was dosed on a flat scale of 125 mg (1 capsule x 100 mg/day, 1 capsule x25 mg/day) will be administrated orally o.d on a 21 days on / 7 days off dosing schedule. One cycle is considered to consist of 4 weeks of PD-0332991 administration.

Patients should be instructed to administrate PD-0332991 with a sufficient amount of water at least 1 hour prior to a meal or at least 2 hours following a meal and to swallow the required number of capsules at approximately the same time on each day.

PD 0332991

Antoine Italiano, MD/PhD

The treatment of advanced GIST patients is based on imatinib followed with sunitinib in case of resistance/intolerance. However, the median progression-free survival (PFS) on sunitinib is frequently short, and after failure with both imatinib and sunitinib, treatment remains controversial.

Previous studies on GISTs have linked 9p21 alterations to tumor progression (El-Rifai et al. 2000; Kim et al., 2000; Schneider-Stock et al., 2003; Schneider-Stock et al., 2005; Romeo et al. 2009; Haller et al., 2008) but the driver gene was not positively identified (CDKN2A, CDKN2B, or MTAP) (Astolfi et al., 2010; Belinsky et al., 2009; Perrone et al., 2005; Assamaki et al. 2007; Huang et al., 2009). A recent study has shown that homozygous 9p21 deletions target CDKN2A and more specifically p16INK4a 4. Most of the CINSARC genes are known to be under the transcriptional control of E2F. RB1 sequesters E2F, which is released from the complex upon RB1 phosphorylation by CDK4. CDK4 is, in turn, inhibited by p16INK4a. Hence, we hypothesize that alteration of the restriction point via deletion of p16INK4a (and more rarely of RB1: 20% of cases) gene in GISTs is likely to be a causative event that leads to the overexpression of CINSARC genes, which in turn induce chromosome instability and ultimately metastasis. Low p16INK4a expression was associated with response to PD-0332991 in several in vitro tumor model(Konecny et al. 2011; Katsumi et al. 2011; Finn et al. 2009). Considering our molecular data, we believed that PD-0332991 warrants clinical investigation in advanced gastrointestinal stromal tumors with alteration of p16INK4a. This alteration is detectable by comparative genomic hybridization which is a technique highly manageable in the context of routine clinical care and clinical trial.

Main objective was to assess the antitumor activity of PD-0332991 in terms of non-progression at 16 weeks (after centralized review) in patients with documented disease progression while on therapy with imatinib and sunitinib for unresectable and/or metastatic GIST.

Medical Conditions : Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib

Study design : Exploratory, one-arm, multicenter, phase II clinical trial based on two-stage Simon's design

Main objective : To assess the antitumor activity of PD-0332991 in terms of non-progression at 16 weeks (after centralized review) in patients with documented disease progression while on therapy with imatinib and sunitinib for unresectable and/or metastatic GIST.

Secondary objectives

* To assess the antitumor activity of PD-0332991 in terms of :

  * Objective response rate (ORR) (as per RECIST v1.1 criteria)
  * Progression-free survival (PFS) (as per RECIST v1.1 criteria)
  * Overall survival
* To assess the safety of PD-0332991

Study drug formulation: PD-0332991 is formulated as gelatin capsules of 100 mg and 25 mg respectively. PD-0332991 was administrated orally. PD-0332991 dosed on a flat scale of 125 mg. PD-0332991 was administrated on a 21 days on / 7 days off dosing schedule. One cycle was considered to consist of 4 weeks of PD-0332991 administration.Patients were treated with PD-0332991 until progression of disease, unacceptable toxicity, death or discontinuation for any other reason.

Tumor assessment and response assessed according to RECIST v1.1, with same type of exam in regard of baseline.

All potential sites of tumor lesions (target and non-target lesions) assessed using MRI or CT Scan with IV contrast of the Thorax Abdomen and Pelvis using a 5mm slice thickness with a contiguous reconstruction algorithm (a PET scan is not acceptable for radiological evaluation).

Evaluation were assessed:

* at baseline within 21 days before the first dose of PD-0332991
* at D(28) of Cycle 1, at D(28) of Cycle 2 then every 8 weeks until month six and then every 12 weeks until disease progression or starting other treatment.

Response regarding the first endpoint was assessed by central radiology review. Whenever the criteria of response are met (Complete Response (CR) or Partial Response (PR)), the appropriate imaging tests were repeated at least four weeks later in order to confirm the response.

The decision regarding patient management remained with the local investigator.

optionnal: Fresh tumor biopsies FFPE (Formalin-Fixed Paraffin-Embedded) at screening and at Day 21 of Cycle 1 are encouraged to be collected. Once collected, the samples may be profiled by IHC, and array gene expression analysis

Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib

Efficacy and Safety of PD-0332991 in Patients With Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Phase 2 Study

Efficacy is assessed based on 4-month non progression. Non progression is defined as complete or partial response (CR, PR) or stable disease (SD), using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Non-progression rate will be calculated as the number of alive and progression free patients divided by the number of eligible and assessable patients for the efficacy analysis. Eligible and assessable populations are described in corresponding section of protocol. As recommended by RECIST v1.1, all claimed response will be centrally reviewed by an expert of the study. The results of the centralized radiological review will be used for the analysis of the primary endpoint.

Objective response is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 Efficacy is assessed based on objective response at 4-month. Objective response is defined as complete or partial response (CR, PR) using the Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Objective reponse will be calculated as the number of alive patients with objective reponse divided by the number of eligible and assessable patients for the efficacy analysis. Eligible and assessable populations are described in corresponding section of protocol. As recommended by RECIST v1.1, all claimed response will be centrally reviewed by an expert of the study. The results of the centralized radiological review will be used for the analysis.

Progression-free survival time is defined as the time from the first administration of treatment to progression (as per RECIST v1.1) or death of any cause, whichever occurs first.

Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Overall survival is defined as the time from the first administration of treatment to death.

Institut Bergonié

Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib.

PD-0332991 is formulated as gelatin capsules of 100 mg and 25 mg respectively.

PD-0332991 will be administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively.: PD-0332991 dosed on a flat scale of 125 mg (1 capsule x 100 mg/day, 1 capsule x25 mg/day) will be administrated orally o.d on a 21 days on / 7 days off dosing schedule. One cycle is considered to consist of 4 weeks of PD-0332991 administration.

Patients should be instructed to administrate PD-0332991 with a sufficient amount of water at least 1 hour prior to a meal or at least 2 hours following a meal and to swallow the required number of capsules at approximately the same time on each day.

PD-0332991

Age, Continuous

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

France

Region of Enrollment

Pr Antoine Italiano

Population evaluable for efficacy: All patients eligible and for whom the following conditions are satisfied:

(i) Received at least one complete or two incomplete treatment cycles, (ii) At least one disease measurement recorded not less than four weeks after treatment onset.

Number of Participants With Non Progression at 4 Months

Number of Participants With Objective Response at 4 Months

Efficacy Assessment of PD-0332991 in Terms of Progression-free Survival Time

Efficacy Assessment of PD-0332991 in Terms of Overall Survival Time

Overall Study

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pharmaceutical Solutions

Cetuximab

Antineoplastic Agents, Immunological

DCC-3116 tablets in escalating dose cohorts in 28-day cycles will be administered in combination with encorafenib once daily (QD) and cetuximab once every 2 weeks (Q2W).

DCC-3116 tablets will be administered in combination with encorafenib and cetuximab in 28-day cycles to evaluate preliminary efficacy in participants with 2nd- or 3rd-line BRAF V600E mutated colorectal cancer (CRC).

DCC-3116 tablets in escalating dose cohorts in 28-day cycles will be administered in combination with ripretinib once daily (QD).

DCC-3116 tablets will be administered in combination with ripretinib in 28-day cycles to evaluate preliminary efficacy in participants with 2nd-line advanced gastrointestinal stromal tumor (GIST).

DCC-3116

Ripretinib

Encorafenib

Clinical Team

Jacqueline Banuelos

Arun Singh, MD

Nailet Bestard

Jonathan C Trent, MD, PhD

Julie Burns

Sreenivasa Chandana, M.D., Ph.D.

Phase 1 Screening

Pragya Khadka

Melessa Hardayal

Ping Chi, MD, PhD

Cancer Answer

Knight Cancer Institute Clinical Trials

Refiola Memushi

Margaret von Mehren, MD

This is a Phase 1/2, multicenter, open-label (unless otherwise specified in a combination-specific module) study of DCC-3116 in combination with anticancer therapies. Modules within the master protocol are defined according to different combinations of DCC-3116 with other anticancer agents.

A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies

A Master Protocol for the Multi-Cohort, Phase 1/2 Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies

Identify the observed adverse events and serious adverse events associated with DCC-3116 in combination with cetuximab and encorafenib or ripretinib.

Identify the dose-limiting toxicities for each dose level tested and determine the recommended Phase 2 doses of DCC-3116 in combination with cetuximab and encorafenib or ripretinib.

Proportion of participants who achieve CR or PR per RECIST (or mRECIST, as applicable) v1.1.

DoR is defined as the time interval from the time that the measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death, whichever occurs first.

The DCR is defined as the proportion of participants who achieve CR, PR, or stable disease \[SD\] at the specified time point per RECIST (or mRECIST, as applicable) v1.1.

Time to response is defined as the time from initiation of treatment until the first assessment demonstrating CR or PR per RECIST (or mRECIST, as applicable) v1.1.

PFS is defined as the time from initiation of treatment until documented disease progression per RECIST (or mRECIST, as applicable) v1.1 or death, whichever occurs first.

OS is defined as the time from initiation of treatment until death.

Measure the maximum observed concentration of DCC-3116 combinations.

Measure the time to maximum plasma concentration of DCC-3116 combinations.

Measure the minimum observed concentration of DCC-3116 combinations.

Measure the AUC of DCC-3116 combinations.

Pfizer

Deciphera Pharmaceuticals LLC

Escalation Module A Part 1 DCC-3116 combination closed on January 8, 2024, with no participants enrolled.

Expansion Module A Part 2 DCC-3116 combination closed on January 8, 2024, with no participants enrolled.

Identify the observed adverse events and serious adverse events associated with DCC-3116 in combination with other anticancer therapies.

Identify the dose-limiting toxicities for each dose level tested and determine the recommended Phase 2 doses of DCC-3116 in combination with other anticancer therapies.

Proportion of participants who achieve CR or PR per histology-specific consensus response criteria.

DoR is defined as the time interval from the time that the measurement criteria are first met for CR or PR (whichever is first recorded) per histology-specific consensus response criteria until the first date that the progressive disease is objectively documented or death, whichever occurs first.

The DCR is defined as the proportion of participants who achieve CR, PR, or stable disease (SD) per histology-specific consensus response criteria.

Time to response is defined as the time from initiation of treatment until the first assessment demonstrating CR or PR per histology-specific consensus response criteria.

PFS is defined as the time from initiation of treatment until documented disease progression per histology-specific consensus response criteria or death, whichever occurs first.

Symptoms and General Pathology

Neoplasm Metastasis

Tin Fluorides

Growth Inhibitors

Angiogenesis Inhibitors

Participants will receive both CGT9486 and sunitinib orally until study stopping rules are met.

CGT9486 plus sunitinib

Participants will receive CGT9486 until steady state then both CGT9486 and sunitinib orally until study stopping rules are met.

CGT9486

Participants will receive sunitinib until steady state then both sunitinib and CGT9486 orally until study stopping rules are met.

Participants will receive sunitinib orally until study stopping rules are met.

Cogent Biosciences

Jessica Sachs, MD

This is a Phase 3, open-label, international, multicenter study of CGT9486 in combination with sunitinib. This is a multi-part study that will enroll approximately 426 patients. Part 1 consists of two evaluations: 1) confirming the dose of an updated formulation of CGT9486 to be used in subsequent parts in approximately 20 patients who have received at least one prior line of therapy for GIST and 2) evaluating for drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who have received at least two prior tyrosine kinase inhibitors (TKIs) for GISTs. The second part of the study will enroll approximately 388 patients who are intolerant to, or who failed prior treatment with imatinib only and will compare the efficacy of CGT9486 plus sunitinib to sunitinib alone with patients being randomized in a 1:1 manner.

This is a multi-part study: Part 1a is a single-arm design, Part 1b is a two-arm parallel design drug-drug interaction evaluation in the first treatment cycle and single-arm design in subsequent treatment cycles, and Part 2 is a randomized two-arm parallel comparator study

(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors

A Phase 3 Randomized, Open-Label, Multicenter Clinical Study of CGT9486+Sunitinib vs. Sunitinib in Subjects With Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumors

Area under the plasma concentration-time curve (AUC)

Time to maximum observed plasma concentration (Tmax)

Time from first dose to documented disease progression or death due to any cause, whichever occurs first

Incidence and severity of Adverse Events from first dose of study drug

Incidence and severity of Serious Adverse Events from first dose of study drug

Incidence of Adverse Events leading to dose modifications from first dose of study drug

Change from baseline in laboratory results

Time from first dose to death due to any cause

Percentage of subjects who achieved documented complete response (CR) + confirmed partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Percentage of subjects who achieved CR + PR + stable disease (SD) at 16 weeks

Time from first dose to first documented response based on modified Response Evaluation Criteria in Solid Tumors Version 1.1

Time from first response (CR or PR) to the date of progression or death from any cause, whichever occurs first

Change in individual scores in patients with locally advanced, unresectable, or metastatic GIST treated with CGT9486 in combination with sunitinib compared with patients treated with sunitinib monotherapy. The scale comprises 30 questions, 24 of which are aggregated into 9 multi-item scales, to include 5 functioning scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain and nausea/vomiting) and 1 global health status scale. The remaining 6 single-item scales assess symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea and the financial impact). All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status denote a better level of functioning, while higher scores on the symptom and single-item scales indicate a higher level of symptoms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib	NCT01907607	Advanced Gastro...	PD 0332991	18 Years -	Institut Bergonié
A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies	NCT05957367	Colorectal Canc... GIST	DCC-3116 Ripretinib Cetuximab Encorafenib	18 Years -	Deciphera Pharmaceuticals LLC
A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies	NCT05957367	GIST	DCC-3116 Ripretinib	18 Years -	Deciphera Pharmaceuticals LLC
(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors	NCT05208047	Advanced Gastro... Metastatic Canc...	CGT9486 plus su... CGT9486 Sunitinib Sunitinib	18 Years -	Cogent Biosciences, Inc.
A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies	NCT05957367	Colorectal Canc... GIST	DCC-3116 Ripretinib Cetuximab Encorafenib	18 Years -	Deciphera Pharmaceuticals LLC

Spots Global Cancer Trial Database for advanced gastrointestinal stromal tumors